Over the course of the two decades it’s been on, Grey’s Anatomy becoming known for killing off its main characters, some of its most upsetting departures involved key characters brutally dying, or doing so gratuitously, as their exits were already set up.

However, some departures were upsetting even if the characters leaving didn’t end their Grey’s Anatomy story dead, but their departure greatly changed the medical drama or impacted other characters extremely negatively. This was the case for at least two original interns’ exits. Some characters’ centrality ensured that their departure could have only entailed their death, as it would have been unbelievable that they’d stay away after their role in the medical drama. Other departures proved upsetting because of how incredibly unfair it was for their storylines to end like that, making Grey’s Anatomy’s most upsetting departures so for different reasons.

8 Lexie Grey

Lexie's Death Is Among The Saddest Ever In Grey's Anatomy's Most Traumatic Episode

Lexie Grey’s departure deserves its spot among the most upsetting because of how and when her death happens. In Grey’s Anatomy season 8, episode 24, dubbed the most traumatic episode in the entire series, Meredith, Derek, Lexie, Mark, Arizona and Cristina go through a plane crash and spend the whole episode lost in the woods, trying to find the others and take care of each other’s wounds. Lexie is the only one to die at the crash site.

Finding herself where the back part of the plane was unlike the other doctors, Lexie succumbed to injuries in her left arm, pelvis and legs.

Lexie’s departure manages to be heartbreaking due to it happening during an episode where everyone is under an incredible amount of stress, and because of how it happens. Lexie being pinned by parts of the plane makes her emotional death hard to watch, made more heartbreaking by Mark’s love confession and Meredith and Cristina only getting to them after Lexie’s last breath.

7 Derek Shepherd

Derek's Death Was Heartbreaking & Changed Grey's Anatomy As It Was Known

Derek’s departure is another one that is particularly difficult to deal with, after a season when the possibility of Meredith and Derek breaking up is explored, only to conclude Derek’s story in the sole way to save his marriage to Meredith. Another unexpected death, Derek’s departure allows him to spend his last day alive as a hero, keeping his patients alive until the arrival of the emergency services.

Derek dying in the aftermath of his car accident is exceptionally upsetting because his doctors make one mistake after another in their treatment of him. Derek’s inner monologue highlights their every mistake to the audience, while he can’t speak due to his injuries, so his doctors do not change their treatment. Although Derek’s departure could have only ended in his death, as other avenues would have cheapened his and Meredith’s relationship, their final moments together are nevertheless among Grey’s Anatomy’s most excruciating.

6 Cristina Yang

Cristina's Departure Meant The End Of 1 Key Grey's Anatomy Story

One of the few departures not involving the character dying, Cristina’s still proves incredibly upsetting. Between the attack at the mall making everyone worried about Cristina being there and Cristina’s departure coming after an entire season of fighting between her and Meredith, the odd pacing of Grey’s Anatomy season 10’s finale perfectly depicts why that goodbye feels more epochal than others.

Although Cristina’s departure coincides with her making her dreams come true, as she leaves Grey Sloan Memorial to be the director of cardiothoracic surgery at the Klausman Institute for Medical Research, her exit leaves a hole in the medical drama. Meredith and Cristina’s friendship has been as central to Grey’s Anatomy as very few others, making Cristina’s departure mean that the medical drama will have to drastically change as a result of her exit. Cristina still being missed makes that the case, even if Meredith took to heart Cristina’s most important advice.

5 George O'Malley

John Doe Being Revealed To Be George Is 1 Of Grey's Anatomy's Most Shocking Developments

Easily among Grey’s Anatomy’s most upsetting exits, George’s departure is already set up when he dies, as he had decided to enlist while his loved ones planned to convince him not to go. The nature of his whereabouts being unknown and the day ing by with George being impossible to find make George’s last episode extremely chaotic, until the final revelation that their patient John Doe was George through his writing “007” on Meredith’s hand shocks Seattle Grace’s doctors and audiences.

How unfair it also feels, given how George could have just gone overseas as planned, makes it still one of the most upsetting departures in Grey’s Anatomy.

George’s death marks the first big exit of a main character, and its happening at the same time Izzie is also risking her life makes it all the more painful. How unfair it also feels, given how George could have just gone overseas as planned, makes it still one of the most upsetting departures in Grey’s Anatomy, 16 years after it happened.

4 Ellis Grey

How Ellis's Death Was Intertwined With Meredith Almost Dying Makes It Wholly Upsetting

Ellis Grey has never been one of Grey’s Anatomy’s most loved characters due to her conflictual relationship with Meredith and the vivid feeling that Ellis hated Meredith in Grey’s Anatomy. Even after her death, Ellis’s relationship with her daughter Meredith continues to be explored, making her one of the medical drama’s most important characters. The difficult relationship between Meredith and Ellis makes Ellis’s death exceptionally upsetting.

One of the last things Ellis shares with Meredith while lucid is her disappointment in seeing Meredith is “no more than ordinary” after she raised her to be an extraordinary human being.

Happening in Grey’s Anatomy season 3, Ellis ends up at Seattle Grace after collapsing at her care home. Her rare moments of lucidity when she is in the hospital lead to one of the worst fights with Meredith during which she calls her ordinary. Meredith almost drowning happening at the same time Ellis is at Seattle Grace nevertheless makes Ellis’s departure upsetting, as the two meet in Meredith’s dreams, with Ellis coming towards Meredith signifying her dying, while simultaneously pushing Meredith to live.

3 Denny Duquette

Denny's Was Grey's Anatomy's First Important & Unexpected Death

Denny Duquette’s is one of Grey’s Anatomy’s first major deaths, with his departure being too unexpected after Izzie even cut his LVAD to make him worse, so that that would make UNOS give the heart to Denny instead of Erika’s patient. While Denny only becomes important in the context of his relationship with Izzie, his departure is wholly upsetting because of his story up until his death.

Denny’s departure is a major Grey’s Anatomy season 2 development and impacts season 3 and beyond, making it easy to understand the reason for how upsetting it is.

Indeed, Izzie going to great lengths to secure Denny his transplant hints at their story ending happily, especially after Denny’s surgery goes well and he and Izzie agree she would come by in her dress to say hi before the hospital prom. However, tragedy strikes when nobody is paying attention to Denny anymore, and a stroke effectively kills him. Denny’s departure is a major Grey’s Anatomy season 2 development and impacts season 3 and beyond, making it easy to understand the reason for how upsetting it is.

2 Andrew DeLuca

The Consequences Of Andrew's Death Were Felt In Both Grey's Anatomy & Station 19

Andrew DeLuca’s is another departure marred by how upsetting his final moments are. After exhibiting signs of mania but also successfully diagnosing Richard’s problem, Andrew’s Grey’s Anatomy season 17 is characterized by his certainty about one of his patients being trafficked. Everyone at Grey Sloan Memorial takes Andrew’s accusations as a sign he wasn’t okay again, but his ending storyline in Grey’s Anatomy and Station 19 vindicates him.

Andrew’s departure lets him go out as a hero, risking his life to save multiple girls from a trafficking ring, and his investigation effectively makes it possible for authorities to apprehend everyone involved. Still, how heartbreaking Andrew’s final moments with Carina and everyone at Grey Sloan are makes his departure difficult to watch. How Andrew’s death affects Carina's own story in Station 19 makes everything even sadder, easily making his departure earn a place among the most upsetting.

1 Alex Karev

Alex's Abrupt Departure & How It Left Jo Makes It Unbelievably Upsetting

Another departure not entailing the character’s death, Alex’s earns its place among the most upsetting because of how his departure happens. Indeed, Alex’s last episode doesn’t even feature him onscreen, as the last time he was seen was during Meredith’s medical license hearing in Grey’s Anatomy season 16, episode 8. His choice to leave Seattle and Jo unexpectedly, without telling Jo and Meredith what had happened face-to-face, easily makes his exit one of the most infuriating.

All the seasons of Grey’s Anatomy until season 21 are available to stream on Hulu.

Alex’s exit in Grey’s Anatomy season 16 involving a reunion with Izzie and their biological kids makes everything more puzzling in light of his finally being happy with Jo. His decision emotionally destroys Jo in the following seasons, easily making Alex’s exit among the most upsetting and his decision one of the least easy to forgive throughout Grey’s Anatomy.

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