George Simmons, portrayed by Adam Sandler, is a successful comedian and actor in his forties, but beneath his fame, he grapples with profound loneliness and estrangement from his loved ones. After receiving a diagnosis of acute Myeloid leukemia, he learns about an experimental treatment that holds only an eight-percent chance of success. Confronted with the possibility of his own mortality, George decides to reconnect with his passion for stand-up comedy. Meanwhile, aspiring comedian Ira Wright, played by Seth Rogen, shares an apartment in Los Angeles with his two close friends, Mark Taylor Jackson and Leo Koenig, portrayed by Jason Schwartzman and Jonah Hill. Mark boasts about his leading role in a sitcom, Yo Teach, despite its flaws, continually bragging about his financial success.
One day, Mark generously claims he will refrain from pursuing his romantic interest, Daisy, played by Aubrey Plaza, for ten days to give Ira the chance to impress her. At a comedy club, George delivers a darkly humorous routine, which Ira later mockingly critiques in his own performance. This leads George to reach out to Ira the following morning, requesting his help in crafting jokes for an upcoming gig at a corporate event.
As George's assistant, Ira learns about George's serious illness, and he takes on the responsibility of caring for him during treatment. Encouraging George to open up about his condition, Ira helps him reconnect with his past. George also makes a call to his ex-fiance, Laura, portrayed by Leslie Mann, to express regret over their past, although he withholds the details of his situation.
Complicating matters, Ira discovers that Daisy and Mark have been intimate and decides to sever all ties with her. Meanwhile, upon learning about George's illness, Laura visits him, revealing her own struggles with her husband, Clarke, and the infidelity she has endured. Their reunion paves the way for a tentative friendship, which is further complicated when George learns that his leukemia is in remission.
As George adjusts to his new reality, he realizes he wants a long-term relationship and contacts Laura, though he does not share his good news. A series of events lead to a comedic yet poignant reunion, where George, Ira, and Laura navigate the complexities of their relationships while George attempts to maintain the facade of being ill when Laura's husband arrives unexpectedly. Tension escalates as Laura confronts Clarke about his own infidelities, leading to a heartfelt decision about her marriage.
In the aftermath, George finds himself grappling with the consequences of their choices, including the end of his friendship with Ira when he feels betrayed. As Ira reflects on George's refusal to learn from his experiences, he returns to his old job while simultaneously pursuing a relationship with Daisy. The story culminates with George witnessing Ira's growth in confidence on stage and seeks reconciliation, acknowledging that while he may no longer be sick, he must work on becoming a better person. The film closes with a heartwarming moment of laughter and camaraderie between George and Ira as they share jokes, symbolizing the repair of their friendship amidst the chaos of life.
