The film opens with a stand-up comedy bit from Kumail Nanjiani (Kumail Nanjiani) talking about how life growing up in Pakistan is not much different from life in America, other than arranged marriages, playing cricket instead of baseball, and the fact that they get old TV shows like "Knight Rider" around this time.
Between stand-up gigs, Kumail is an Uber driver in Chicago. He frequently performs with his fellow comics CJ (Bo Burnham), Mary (Andy Bryant), and Chris (Kurt Braunohler). At their comedy club spot, they spot a recruiter named Bob Dalavan (Jeremy Shamos), who is looking for comedians to headline his upcoming Montreal Showcase. Kumail and his friends really want to get in, but they all acknowledge that Chris is the least funny of all of them.
During one of Kumail's performances, he gets cheered on by a young woman in the audience named Emily Gardner (Zoe Kazan). After the show, Kumail approaches Emily and politely tells her that she heckled him and it's rude to heckle comedians, but Emily defends herself by stating she only gave him a "woo-hoo!" Kumail then writes Emily's name in Urdu. They start talking, and Emily tells Kumail she is studying to be a therapist. Soon enough, Kumail takes Emily home and they watch a movie before having sex. Emily regrets having sex on the first date and she calls for an Uber...and the nearest driver is Kumail.
Kumail later has dinner with his parents Azmat (Anupam Kher) and Sharmeen (Zenobia Shroff), and his brother Naveed (Adeel Akhtar) and his wife Fatima (Shenaz Treasury). Sharmeen frequently sets Kumail up with other Pakistani women in really unsubtle ways to get him to marry one of them. He keeps all of their pictures in a cigar box despite having absolutely no interest in any of these women.
Kumail continues to see Emily without his family knowing. She attends his one-man show with her friend Jesse (Rebecca Naomi Jones), which is essentially a lecture of Pakistan's history and culture. He brings her back to his apartment to watch a movie but they just hook up again. Late at night, Emily tells Kumail she wants to go to the diner across the street for some coffee. When Kumail continues to question her, Emily admits that she really needs to "take a shit" and is just too embarrassed to do it there since Kumail has no matches or air freshener. Kumail decides to sit outside the building until Emily is done. He takes her home and she says they shouldn't call each other again. Kumail calls her almost immediately and she invites him upstairs.
Kumail goes out with Naveed to the batting cages. During lunch, Kumail tells Naveed that he is dating a white woman. Naveed is surprised and insists that Kumail follow the same tradition as he did in marrying a Pakistani woman. Naveed refers to one of their cousins who was disowned by the family because he chose to marry an Irish woman.
Kumail and Emily go grocery-shopping. At one point, Emily complains about an ache in her foot after she twisting it slightly during a dance class.
Emily is in Kumail's apartment and finds the cigar box with all the women his mother tried to set him up with. When she questions him about it, he reveals the whole arranged marriage deal, and also that his family doesn't know about her because he is worried that they will disown him as well. Emily is angry and hurt by Kumail's lies and she storms out of his apartment.
Kumail performs again later that night and takes home another woman after writing her name in Urdu. He gets a phone call from Jesse, urging Kumail to go to the hospital because Emily has been admitted due to a sickness.
Kumail shows up to the hospital and finds Emily, who is not happy to see him. The doctor pulls Kumail out to tell him that Emily has an infection in her lungs and that they need to put her in a medically-induced coma. Despite not being her husband, Kumail signs off on the coma for Emily's sake. He then uses Emily's thumb to unlock her phone so he can call her parents and tell them what has happened.
Emily's parents, Beth (Holly Hunter) and Terry (Ray Romano), arrive at the hospital in the morning after Kumail has spent the night there. Beth knows about Kumail from what Emily has told them, and she is not happy to see him. Terry is slightly more accepting of Kumail calling them and making sure Emily is taken care of. Although Kumail attempts to hang around with Emily's parents, Beth is not willing to let him get close, claiming he screwed up with Emily.
The doctors tell Kumail, Beth, and Terry that they will need to keep Emily in the coma until they remove the infection from her lungs. Terry invites Kumail to sit with him and Beth as they have lunch in the hospital cafeteria. Terry makes it awkward by trying to talk to Kumail about 9/11.
Beth and Terry stay at Emily's apartment until they hear updates on their daughter's condition. Kumail tries to get out of spending time with them by saying he is going to be headlining a comedy show that night. Terry decides to go to take his mind off Emily's condition, and he invites a reluctant Beth. Kumail performs the show, and he sees that Beth and Terry are laughing and enjoying it. A heckler then tells Kumail to go back to ISIS. After an awkward silence, Beth calls out the heckler and nearly fights with him until she is pulled out of the club.
Back at Emily's apartment, Terry is sleeping while Beth shows Kumail embarrassing pictures of Emily in high school when she was a goth. Beth then mentions details about her and Terry's relationship.
At Kumail's family's house, Sharmeen introduces Kumail to a young woman named Khadija (Vella Lovell). She entertains the family with a trick where she draws sunglasses on Andrew Jackson's head on a $20 bill, then having the shades slide down his face. After spending a night with Khadija and her parents, Kumail takes her home. Khadija asks Kumail if he wants to hang out, but he lets her down gently and says they wouldn't work together because he loves someone else. Khadija is hurt and she goes back into her house before insulting "The X-Files", which is Kumail's favorite show.
Kumail, Beth, and Terry learn from the doctors that they need to keep Emily in the coma longer than expected. Beth becomes worried and considers moving Emily to a different hospital. Kumail speaks to a nurse about this, and she says that would not be good for Emily at this stage. Beth and Terry get into a fight because Beth thinks Terry is too scared to come to a decision.
Terry stays at Kumail's apartment for the night. He admits to Kumail that he once had a one-night stand behind Beth's back, but he felt so guilty that he ended up telling her what he did. Terry says that's how he knew he really loved Beth, since he felt like shit after what he did.
In the morning, Kumail finds a note from Terry saying he is going to the hospital. When Kumail gets there, he finds Beth and Terry preparing to sign off on moving Emily to another hospital. Despite Kumail pleading and objecting, the two insist they are doing what's best for their daughter.
Kumail's parents show up at his apartment to demand to know what is going on with him in regards to him rejecting Khadija. Kumail becomes frustrated and admits to them that he is in love with a white woman; Emily. Predictably, Sharmeen explicitly disowns Kumail, and Azmat tells Kumail he is being selfish for trying to look out for himself and not consider the feelings of those around him.
Kumail goes to a fast food restaurant asking specifically for four slices of cheese on one burger. When he's told that they can't do that, Kumail flips out and screams obscenities at the guy behind the window before throwing a garbage bin around. He then apologizes and just gets his food. As he eats, he gets a text reminding him that he is going up for the Montreal Showcase in less than 20 minutes.
Kumail arrives at the comedy club for the show, clearly not ready to perform. He goes up onstage and starts to tell jokes, but he quickly breaks down and talks about Emily being in a coma, unable to hold back tears or keep his act together. Afterwards, he visits Emily at the hospital and gently tells her it's okay if she wants to let go now.
The next day, Kumail gets a text from Terry telling him to go to the hospital. When Kumail gets there, he finds that Emily is awake, sitting with Beth and Terry. The three are told by a doctor that Emily's disease causes her body to think she's sick and is fighting against an otherwise harmless ailment. When they leave the room, Kumail goes to talk to Emily, but she is still mad at him for what happened before she went comatose. She says Kumail makes her feel sad and she doesn't want to see him. Kumail dejectedly leaves. He passes Beth and says it's crazy that they went through something together and that they probably won't see each other again. Beth says maybe it doesn't have to be like that.
Beth and Terry host a welcome-home party for Emily. Kumail shows up with a gift and talks to Emily in private. He claims that he's changed and wants her to take him back. Emily argues that he only came to this realization when she was sick and that she doesn't think it's fair for either of them to pursue something they don't feel mutually.
Kumail returns to the comedy club after his disastrous performance. CJ and Mary tell Kumail they are moving to New York City and they want him to join them so they can continue doing comedy over there.
Kumail goes to his parents' house. Everyone, including Naveed and Fatima, is giving him the silent treatment. Kumail has prepared cards to anticipate their responses to try and break the tension. He insists that he will not be kicked out of the family because he is technically part of the family and the decision should be unanimous. The family continues to stay silent.
Life continues to go on for everyone. Kumail continues to perform stand-up and his one man show. Emily goes through physical therapy. Beth and Terry are able to sleep in the same bed together again. Emily watches a video of Kumail bombing as he talks about her, knowing what he said about her was sincere. Beth talks to Emily about how Kumail was there for her the whole time.
Kumail is getting ready to move with CJ and Mary. A car pulls up across the street. Azmat comes up to Kumail with a container filled with Kumail's favorite home-cooked meal. Sharmeen still refuses to talk to or even look at Kumail. Azmat still insists that Kumail is kicked out, but he wishes his son good luck as he moves.
Kumail is now performing in an NYC comedy club. In the middle of his bit, he hears a "woo-hoo!" It's Emily with some friends. They have the same exchange they had about heckling when they first met, and Kumail asks what brings her to New York. Emily says she is there to see someone. The two then share a hopeful and loving smile.
The closing credits feature pictures of the real Kumail Nanjiani with his wife Emily V. Gordon (whom Movie-Emily is based off of), and their traditional Pakistani wedding with Kumail's brother and parents standing next to them.