The film begins with a comedic routine by Kumail Nanjiani, who humorously reflects on the similarities between life in Pakistan and America, highlighting the distinct cultural aspects like arranged marriages and sports preferences, notably cricket over baseball. Amid his stand-up gigs, Kumail works as an Uber driver in Chicago, where he hangs out with fellow comedians such as Aidy Bryant, Chris (Kurt Braunohler), and CJ ([Bo Burnham]).

One evening, as they perform at a comedy club, they catch the attention of a talent recruiter named Bob Dalavan (Jeremy Shamos), who is scouting for comedians for a Montreal Showcase. Though they all aspire to get in, it’s acknowledged that Chris has the least comedic talent in the group.

During one of his sets, Kumail is heckled—not in a mean way—by a vibrant audience member named Emily Gardner. After the show, Kumail approaches her to humorously address the heckling, but Emily insists she only cheered for him. They quickly bond over shared interests, and Kumail even writes her name in Urdu. Their connection deepens quickly, leading to a romantic encounter, but Emily later feels regret and requests an Uber, unknowingly ordering it from Kumail.

Kumail’s complex family life introduces tension; during dinner with his parents Azmat Kher and Sharmeen, along with his brother Naveed and his wife, Sharmeen openly pressures Kumail to settle down with potential brides she has preselected. Kumail secretly continues to date Emily, keeping their relationship hidden from his family, which adds a layer of secrecy and anxiety.

Despite his family’s expectations, Kumail enjoys moments with Emily like grocery shopping, but the relationship faces a major hurdle when Emily discovers the cigar box filled with pictures of women his mother tried to set him up with. Feeling betrayed, Emily confronts Kumail about his family’s traditions and the secrecy, leading to a heated argument which results in her storming out.

The tides turn dramatically when Kumail receives a phone call informing him that Emily has been hospitalized due to a serious lung infection. In a show of devotion, he makes the difficult decision to sign the medical paperwork that places Emily in a medically-induced coma. When her parents, Beth and Terry, arrive, tension fills the hospital as emotions run high, with Beth being particularly unwelcoming towards Kumail.

As days unfold, Kumail grows closer to Beth and Terry, sharing humorous moments and even performing comedy while grappling with the challenges of Emily’s health crisis. In a touching scene, Kumail’s comedic performance brings laughter to Beth and Terry, who begin to warm up to him throughout the stressful ordeal.

Meanwhile, Kumail faces familial rejection, struggling with his love for Emily against the backdrop of his family’s traditional expectations. After finding himself in a comedic rut, Kumail opens up on stage candidly about his feelings for Emily in the midst of an emotional breakdown, showcasing his vulnerable side.

Eventually, after a dark journey through emotional turmoil, Kumail receives a text that Emily has awoken from her coma. However, the reunion is fraught with unresolved emotions as Emily expresses her unhappiness with Kumail’s earlier deceptions. Their conversations reveal the complexities of their feelings, urging Kumail to reflect on his actions and how they have impacted their relationship.

As the film progresses, Kumail navigates his family dynamics and professional aspirations. His journey leads him to a poignant moment when he prepares to leave Chicago to follow his dreams in New York City. In an unexpected twist, Emily appears at one of his shows, rekindling their connection with a nostalgic “woo-hoo!” echoing their first meeting. The film closes with real-life footage celebrating Kumail’s marriage to Emily V. Gordon, providing a heartfelt conclusion to a journey filled with love, identity, and acceptance.