Grey’s Anatomy: The 15 Most Surprising Plot Twists Throughout the Series

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Grey’s Anatomy remains one of the world’s most well-known and beloved for so many reasons. Its dynamic revolving cast, its emotionally fraught musical selections, and its unbelievable medical storylines continue to keep the attention of forever fans and occasional viewers around the world. Across the show’s run so far, Grey’s has sucked in audiences for almost 20 years since the show’s first episodes in 2005.

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For its 19 seasons – and with the 20th on the horizon to be released in March 2024 – there’s no denying the cultural impact of this show and its longtime grip on its undying popularity. Grey’s is known for its continuously wild twists and turns, always bringing dedicated audiences along for the ride. Here are 15 of the most surprising plot twists throughout the series.

15 George is John Doe

T. R. Knight as George O'Malley in Grey's Anatomy.
ABC

“Now or Never” (Season 5, Episode 24)

“Now or Never” (Season 5, Episode 24) is the final episode of Grey’s Anatomy’s 5th season, wrapping up multiple different storylines from throughout the season. Izzie Stevens had just undergone surgery for her cancer; Meredith Grey and Derek Shepherd are entering into the beginning of their marriage; and George O’Malley had just joined the army. After a John Doe is rushed into the hospital, the doctors discover his devastating identity.

A Heartbreaking Sacrifice

Established fans and one-time viewers alike will never forget how the reveal scene played out. With George on his way out of Seattle Grace to serve his country, his absence felt normal, until Meredith reaches the bedside of the unknown man who had been hit by a bus. John Doe, unrecognizable to anyone else as George, traces “007” in Meredith’s hand, reminding her of his nickname and revealing himself. George saved a woman by jumping in front of a bus, sacrificing his life for hers.

14 Meredith Meets Ellis Between Life and Death

Ellen Pompeo as Meredith Grey and Kate Burton as Ellis Grey in Grey's Anatomy.
ABC

“Some Kind of Miracle” (Season 3, Episode 17)

In “Some Kind of Miracle” (Season 3, Episode 17), audiences get to follow the fallout of Meredith’s drowning during her attempt to save someone after the ferry accident in the third season of Grey’s. With multiple episodes developing this storyline and others surrounding it, Meredith sinks into a limbo-like afterlife for a short time and sees important people who have left her life.

Meredith Lives, but Ellis Dies

When Meredith makes it to the other side (which looks just like a dreamlike version of the hospital), she encounters Denny, Dylan, and her deceased dog, Doc. At the same time, Meredith’s mother, Ellis Grey, struggles in the land of the living, requiring what becomes unsuccessful CPR. Ellis wanders into Meredith’s limbo, and the two meet in a hallway, where Ellis imparts to her daughter how needed and loved she is. Meredith survives and makes it out, but Ellis passes away, making sure she says goodbye to her daughter on her way out.

13 Ava Is Rebecca Pope

Elizabeth Reaser as Ava/Rebecca Pope in Grey's Anatomy.
ABC

“Testing 1-2-3” (Season 3, Episode 24)

In Season 3, Episode 15, “Walk On Water,” the ferryboat accident draws Seattle Grace’s attention for multiple episodes due to the extent of the casualties it caused. Alex Karev assists an injured woman, who is pregnant, wounded in the face, and eventually suffering from severe memory loss. As a Jane Doe, she takes on the name Ava after she chooses the facial reconstruction mold given that name by Alex.

The Significance of This Plot Twist

In “Testing 1-2-3” (Season 3, Episode 24), it’s revealed just how much Ava actually knows about herself. After the birth of her child and the continuation of her amnesia, she begins to have memories return to her, which she conceals from Alex. Yearning for a different life than the tragic one she had lived and forgotten about, she eventually tells Alex her real name and recalls how she is Rebecca Pope.

12 The Plane Crash

Sandra Oh as Cristina Yang, Ellen Pompeo as Meredith Grey, and Patrick Dempsey as Derek Shepherd in Grey's Anatomy.
ABC

“Migration” and “Remember the Time” (Season 8, Episodes 23-26)

Grey’s Anatomy’s plane crash is one of the most formative plot twists throughout the entire series, transforming the lives of those on board and those lucky enough to be spared from the accident. The crash takes place in season 8, between episodes 23 (“Migration”) and 26 (“Remember the Time”) when doctors from Seattle Grace Mercy West traveled to Boise Memorial Hospital to assist in a major surgery.

How This Storyline Changed the Show

So many different plot lines from Grey’s can be considered surprising, but the continuing extent of this one took full advantage of its disastrous nature. The extent of the injuries sustained by those on board would affect characters’ continuing stories, like Arizona Robbins’s loss of her leg. Others weren’t lucky enough to survive; these episodes culminated in the death of Lexie Grey. The survival of the others deepens the connections between the characters featured.

11 The Hospital Shooting

Michael O'Neill as Gary Clark in Grey's Anatomy.
ABC

“Sanctuary” and “Death and All His Friends” (Season 6, Episodes 23 and 24)

Gun violence can affect corners of society that we may think are the safest places possible, including hospitals. In Grey’s Anatomy, the fallout of one man’s rage traumatizes a place of healing. After Gary Clark loses his dying wife earlier in season 6, he reenters the hospital in search of revenge in “Sanctuary” (Episode 23), carrying out his shooting through “Death and All His Friends” (Episode 24).

What Did This Mean for Grey’s Anatomy?

As Meredith and Cristina are initially unaware of what’s going on, Gary seeks revenge against Derek Shepherd, blaming the hospital for his wife’s tragic outcome. He shoots Derek, Reed Adamson, Charles Percy, and multiple others, creating an additional large-scale tragedy out of the personal loss of his wife. The after-effects of this shooting obviously affected the doctors and hospital staff for a long time, causing direct and indirect additional issues as a result.

Related: Grey’s Anatomy: 20 Episodes That Will Make You Cry

10 Christina Covers for Burke’s Injury

Sandra Oh as Cristina Yang and Isaiah Washington in Grey's Anatomy.
ABC

“From a Whisper to a Scream” (Season 3, Episode 9)

As Cristina Yang’s first romantic relationship in the show, her connection to Preston Burke intertwines into a snowball effect of deceit and dishonesty. In the early episodes of Grey’s’ third season, Cristina covers up Burke’s worsening hand tremor that he sustained after getting shot, allowing him to continue to practice medicine and conduct surgeries.

Why Viewers Didn’t See This Coming

Cristina is normally such a straightforward and career-driven character, so it was definitely surprising here to see her compromise her own integrity, the integrity of her partner, and their dedication as surgeons to make sure Burke keeps his job. In “From a Whisper to a Scream” (Season 3, Episode 9), this secret finally falls apart, and Cristina herself opens the can of worms on this carefully concealed part of their lives.

9 Derek Dies

Ellen Pompeo as Meredith Grey and Patrick Dempsey as Derek Shepherd in Grey's Anatomy.
ABC

“How to Save a Life” (Season 11, Episode 21)

From Grey’s Anatomy’s very first season, Meredith romanticizes the initially unattainable McDreamy (who everyone knows as Derek Shepherd). As the show progresses, we know that Meredith and Derek get together and build a beautiful family and life together as the two continue their medical careers. Derek unfortunately meets his tragic end in “How to Save a Life” (Season 11, Episode 21), closing the door on his character’s influential time on Earth.

One of the Most Surprising Deaths on TV

Derek’s death occurs because he chooses to do what he has always done best: helping someone in dire medical need. On a drive to Washington, he comes across a serious auto accident that he can’t ignore, and he makes it a point to assist those injured and affected by it. After they get treatment, as he’s about to leave the scene, Derek gets hit by a semi-truck and loses his life. The reactions of his loved ones after his death combine his adherence to his identity as a helper and his courage to put himself in harm’s way, whether he knew it at first or not.

8 Addison Is Targeted for Providing Abortion Care

Jess Gabor as Tia Marwood and Kate Walsh as Addison Montgomery in Grey's Anatomy.
ABC

“Training Day” (Season 19, Episode 11)

“Training Day” (Season 19, Episode 11) aired in 2023, taking place months after Roe v. Wade was overturned in the United States – the decision that allowed Americans the right to seek abortion care. Addison Montgomery returns to Grey Sloan Memorial Hospital to assist with welcoming trainees under the OB/GYN program. She soon finds herself on the receiving end of rage from outside the clinic after a woman comes to the hospital for an abortion.

Why This Storyline Means so Much

The plot progression in this episode is another important example of how Grey’s addresses real-world issues and realistic complications within the medical world. Actual doctors have indeed experienced harassment (and some still do, in many American states) for providing reproductive medical care, and this instance allows us to see a fictional representation. A brick breaks a window in the clinic, with “Montgomery murders” written on it, kick-starting increasingly aggressive protests surrounding the clinic that involve her staff, as well.

7 Amelia’s Brain Tumor

Kevin McKidd as Owen Hunt and Caterina Scorsone as Amelia Shepherd in Grey's Anatomy.
ABC

“Get Off on the Pain” (Season 14, Episode 2)

Amelia Shepherd, sister to Derek and fellow accomplished neurosurgeon, has her issues. A brain tumor was not something that many of Grey’s viewers may have seen coming, despite her struggles with her behavior and her addiction. “Get Off on the Pain” (Season 14, Episode 2) drops the bombshell that Amelia’s brain is afflicted by a large malignant growth.

How This Twist Took Hold

The aforementioned episode centers around a different brain tumor, at first – belonging to a patient who obviously needs surgery to remove it. Amelia participates in a study driven by Carina on women’s pain, and enters an MRI machine to record the data. When she’s done, she reviews the scan, wondering whose insides contain that massive tumor. Carina and Andrew’s stunned silence allows Amelia to put two and two together – it’s the picture they just took of Amelia’s brain.

6 Adele Is Diagnosed with Alzheimer’s

Loretta Devine as Adele Webber and James Pickens Jr. as Richard Webber in Grey's Anatomy.
ABC

“Golden Hour” (Season 7, Episode 15)

Alzheimer’s disease and Adele Webber, wife to Richard, both commonly appear throughout Grey’s Anatomy, but never together. But in “Golden Hour” (Season 7, Episode 15) through “The Girl with No Name” (Season 8, Episode 20), Adele unfortunately battles the devastating illness that Ellis Grey also went through. This diagnosis changes the sassy and confident Adele for the worse, showing audiences another perspective on how Alzheimer’s can affect people differently.

Why Audiences Were So Surprised

Adele’s character has almost always run the Webbers’ marriage, solidifying her strength and fortitude in so many situations. Her Alzheimer’s diagnosis marks a significant change in her behavior, imparting to viewers the effects that a degenerative brain disease can have on a person’s vitality. Adele’s journey through this is also punctuated by Richard’s kindness towards her and the loving care he offers her, giving her what is best for the rest of her life.

Related: Grey’s Anatomy: 13 Most Outrageous Storylines in the Show

5 Denny’s Death

Katherine Heigl and Jeffrey Dean Morgan as Izzie and Denny in Grey's Anatomy, Denny is dead, lying in bed
ABC
Shondaland

“Losing My Religion” (Season 2, Episode 27)

Throughout season two of Grey’s, Izzie encounters and falls in love with a heart patient at the hospital named Denny Duquette. Desperate to receive a heart transplant, but limited by his condition, he accepts an LVAD wire, which sadly gives him more health complications to deal with. This progression leads to his belief that Izzie would let him die, if she realized the pain he was experiencing.

An Early Shocker for the Series

Izzie’s hand in Denny’s health towards the end of his life (and his death) deserves examining. She cuts Denny’s LVAD wire to ensure that he’ll get a transplant, and he does receive a highly-sought-after heart. Tragically, Denny sustains a blood clot following the surgery, leading to his death. Izzie lies down next to him in his bed, wearing the dress she wanted to marry him in.

4 Stephanie Sets a Fire

Jerrika Hinton as Stephanie Edwards in Grey's Anatomy.
ABC

“True Colors” (Season 13, Episode 23)

Grey’s finales are always known for making sure that both seasons and characters go out with a bang. The name of the show’s final episode in its 13th season, “True Colors” (Episode 23), reveals that horrifying truths will come to light. Two patients enter the ER from the scene of an accident. The woman involved, Alisson, expresses that the man she was rescued with, Keith, sexually assaulted her. Audiences discover that Keith and Dr. Stephanie Edwards are nowhere to be found.

A Shocking Explosion

This turn of events is startling, from start to finish. The added danger of Keith’s revealed identity as a criminal encourages Stephanie to take matters into her own hands. With a child at the hospital also revealed to be in harm’s way, Stephanie encourages the violent Keith to help her out, so they can escape the lockdown. Stephanie ends up dousing Keith in alcohol, which causes him to catch fire, as the nearby oxygen tanks intensify the fire and cause a massive blast.

3 Izzie Discovers She Has Cancer

Justin Chambers as Alex Karev, Katherine Heigl as Izzie Stevens, Ellen Pompeo as Meredith Grey, and Sandra Oh as Cristina Yang in Grey's Anatomy.
ABC

“I Will Follow You Into the Dark” (Season 5, Episode 17)

In season five, Izzie experiences increasingly concerning symptoms, beginning with hallucinating her dead lover, Denny. He says he’s “here for her” – and she doesn’t find out what that statement means until later. After learning she has high levels of LDH and a malignant mole, she pretends that her case is that of the unknown “Patient X,” encouraging the interns under her to figure out what’s really wrong.

Utterly Heart-Wrenching

To allow Izzie to begin this discovery for herself, Denny visits her from the afterlife. In “I Will Follow You Into the Dark” (Season 5, Episode 17), Izzie’s interns conclude that their diagnosis for Patient X is Stage 4 cancer, which she eventually shares with her coworkers and friends. Izzie’s cancer journey is emotionally intense and terrifying for her, but it also became an extremely important aspect of her story and growth as a character.

2 Arizona Cheats on Callie

Sara Ramirez as Callie Torres and Jessica Capshaw as Arizona Robbins in Grey's Anatomy.
ABC

“Readiness is All” (Season 9, Episode 23)

Arizona and Callie Torres marry in season seven after a sharing storied relationship and professional prowess. But Grey’s fans know that the sweetness of their union would be tried by surprising circumstances. In “Readiness is All” (Season 9, Episode 23), Arizona cheats on Callie, choosing another doctor named Lauren Boswell over her loving wife.

Trouble in Paradise

In the beginnings of their relationship, Arizona and Callie are a super cute couple who seem to work well alongside one another. They of course have their challenges (Arizona’s leg, to name one), but Arizona’s character seemed too kind to do that to her partner. This change causes Callie to seek out a divorce, severing her from Arizona until later on in the series.

1 Burke and Cristina’s Almost-Wedding

Isaiah Washington as Preston Burke and Sandra Oh as Cristina Yang in Grey's Anatomy.
ABC

“Didn’t We Almost Have It All?” (Season 3, Episode 25)

The relationship between Preston Burke and Cristina has always been somewhat tumultuous, incorporating secrets, subpar communication, and encouraging both parties to play pretend. Eventually, their deepening connection leads up to their impending wedding in “Didn’t We Almost Have It All?” (Season 3, Episode 25). Before their big moment, Burke’s mom transforms Cristina into a proper Burke woman, leaving her with no eyebrows.

A Wedding Called Off

This subplot was convincing almost up until its final moments. Yes, Cristina was, but it was surely surprising to see this continuation last until the beginning of the wedding itself. As Cristina realizes she’s washed her written vows off her hand, Burke enters the room, apologizing that he tried to make her into someone she isn’t. With that, Meredith takes it upon herself as Cristina’s best friend to call the wedding off, with Cristina still wearing her white gown.

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