Based on the real-life courtship between Kumail Nanjiani and Emily V. Gordon, "The Big Sick" tells the story of Pakistan-born aspiring comedian Kumail (Nanjiani), who connects with grad student Emily (Zoe Kazan) after one of his standup sets. However, what they thought would be just a one-night stand blossoms into the real thing, which complicates the life that is expected of Kumail by his traditional Muslim parents.

When Emily is beset with a mystery illness, it forces Kumail to navigate the medical crisis with her parents, Beth and Terry (Holly Hunter and Ray Romano) who he's never met, while dealing with the emotional tug-of-war between his family and his heart.