PLOTKumail, an Uber driver in Chicago, is a struggling stand-up comedian with a one-man show about his Pakistani American background. His immigrant parents set him up with Pakistani women, expecting that he will follow their example of an arranged marriage, but he is uninterested.
After a show, Kumail has a one-night stand with Emily, a white student, and they begin a relationship. Kumail does not tell his family, fearful they will disown him. After five months, Emily finds photos of the women Kumail’s parents have set him up with. When he tells her he does not know if they have a future, she breaks up with him.
Kumail learns that Emily has been hospitalized; she has a serious lung infection and must be immediately placed in an induced coma. He signs the permission form and calls her parents, Beth and Terry. Aware of their daughter’s messy breakup with Kumail, they tell him he is not needed, but Kumail stays and the three become closer as they deal with Emily’s illness. Beth and Terry attend one of Kumail’s stand-up gigs, during which a racist audience member heckles Kumail, causing Beth to defend him.
Surgery is ineffective and the infection spreads to Emily’s kidneys. Beth wants to transfer Emily to a different hospital, but Kumail and Terry disagree. Beth and Terry argue, and Terry stays at Kumail’s apartment. Terry reveals that he cheated on Beth before and regrets it.
Kumail’s parents visit, angry that he is not taking their marriage suggestions seriously. Kumail tells them that he does not want an arranged marriage and reveals his relationship with Emily. His parents disown him. Before an audition for the Montreal Comedy Festival, Kumail learns that the infection has reached Emily’s heart. Distraught, Kumail tearfully recounts his fears about Emily’s condition and fails the audition.
When Kumail mentions that Emily had an ankle injury that was slow to heal, the doctors realize she has adult-onset Still’s disease, a serious but treatable illness. Emily wakes from her coma and, still pained from their breakup, Emily tells Kumail to leave. Nevertheless, Beth invites Kumail to Emily’s homecoming party. Emily refuses to take Kumail back, reminding him that while he may have had a transformative experience during her illness, from her perspective nothing has changed.
Kumail decides to move to New York City with two comedian friends. He tells his family about his plans and refuses to allow them to reject him. Emily discovers a video of Kumail’s disastrous audition in which he spoke about his feelings for her, and goes to find him after his show. Before she can explain, he tells her he is moving. Emily tells him she appreciates everything he did for her while she was in the coma and wishes him well in New York.
As Kumail prepares to depart, his parents visit. His father tells him they are still angry, but gives him a dish of his favorite food and asks him to stay in touch. As Kumail performs in New York, he is heckled by someone in the crowd; he sees that it is Emily.