George O'Malley is introduced as a fellow surgical intern to Meredith Grey (Ellen Pompeo), Cristina Yang, Izzie Stevens, and Alex Karev; the five of them working under Miranda Bailey. O'Malley and Stevens move in with Meredith, for whom he has romantic feelings but did not express them due to his fear of rejection and the fact that she and one of the attendings Derek Shepherd (Patrick Dempsey) had a mutual interest in one another. On the first day of internship, O'Malley is selected by chief of cardiothoracic surgery Preston Burke (Isaiah Washington) as the first intern to perform surgery. He freezes in the operating room, and is mocked by his peers, and earns the nickname "007" because of almost killing a patient in such a simple operation (referring to James Bond's "licence to kill"). O'Malley dates nurse Olivia Harper, breaking up with her when he contracts syphilis from her, which she in turn contracted from Karev. His friendship with Karev is further strained when the two become trapped in an elevator with a patient who begins to bleed out. Karev freezes, and O'Malley is able to save the patient single-handedly. He goes on to admit his feelings to Meredith, and the two have a one-night stand. When Meredith tells him that sleeping together was a mistake, O'Malley begins avoiding her and starts dating orthopedic surgeon Callie Torres.
During a camping trip, O'Malley learns that Torres has slept with chief of plastic surgery Mark Sloan, and also discovers that Burke is experiencing tremors in his hand. When O'Malley's father is diagnosed with esophageal cancer and a leaking aortic valve, he refuses to allow Burke to operate on him, instead contacting Erica Hahn, Burke's medical school rival. His relationship with Torres is strained when he confronts her about sleeping with Sloan, but he allows her to support him through his father's deteriorating health. Complications from his father's surgery leave him in multi-system organ failure, and his life support is turned off. In an attempt to overcome his grief, O'Malley elopes with Callie to Las Vegas. He later begins to feel that he was mistaken to marry her, and sleeps with Stevens while intoxicated. Stevens confesses that she is in love with him, so O'Malley considers transferring to a different hospital so he can be faithful to his wife. However, he is ineligible to transfer after failing the intern exams. O'Malley decides to repeat his intern year, and confesses to Torres that he slept with Stevens, leading the two to divorce. O'Malley and Stevens embark on a short-lived relationship, only to discover there is no real chemistry between them.
O'Malley moves in with new intern Lexie Grey, Meredith's half-sister. Lexie and O'Malley discover that he only failed his exam by a single point, leading him to confront Richard Webber , the chief of surgery, to ask for a chance to retake the exam. He passes the second attempt, and begins to distance himself from Lexie, who has fallen in love with him. O'Malley supports Stevens when she discovers she has melanoma, and walks her down the aisle as she marries Karev. O'Malley begins to display a talent for trauma surgery, and is told by the chief of trauma surgery Owen Hunt that it is definitely his specialty. He then abruptly and inexplicably decides to join the U.S. Army. While his friends at the hospital prepare an intervention to convince O'Malley to stay, they all work on a severely disfigured John Doe, brought in after a horrible bus accident, in which he pushed a woman out of the way and saved her life. When Meredith goes to check on John Doe, he seems to recognize her and will not let go of her hand. After several attempts at trying, he succeeds in tracing "007" on Meredith's hand. Shocked, she realizes "John Doe" is in fact O'Malley. She informs the other surgeons and they rush him to surgery. However, he flatlines and is ultimately declared braindead. His organs are donated after Stevens confirms that is what O'Malley would have wanted, and he is buried a week later.
