
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.
8Lexie 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.
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.
7Derek 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.
6Cristina 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.

Teddy’s decision to leave Owen represents Cristina’s legacy in Grey’s Anatomy, of women choosing themselves and their dreams over relationships.
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.
5George 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 passing 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.
4Ellis Grey
How Ellis’s Death Was Intertwined With Meredith Almost Dying Makes It Wholly 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.
3Denny Duquette
Denny’s Was Grey’s Anatomy’s First Important & Unexpected 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.
2Andrew DeLuca
The Consequences Of Andrew’s Death Were Felt In Both Grey’s Anatomy & Station 19

There was an ideal way for Grey’s Anatomy to keep Andrew DeLuca alive, but the show ignored it.
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.