Susan Cooper (Melissa McCarthy) is a 40-year-old, single, desk-bound CIA employee who remotely assists her partner, field agent Bradley Fine (Jude Law), on a mission. Fine accidentally kills arms dealer Tihomir Boyanov as he sneezes during a confrontation before extracting the location of a suitcase nuke from him. Susan uncovers evidence that Rayna (Rose Byrne), Boyanov’s daughter, has contacted Sergio De Luca (Bobby Cannavale), a suspected broker with ties to various terrorist groups, so Fine infiltrates her home. However, Rayna shoots Fine dead, while Susan watches helplessly online, then reveals that she knows the identities of the agency’s top agents, including Rick Ford (Jason Statham) and Karen Walker (Morena Baccarin). Susan, who is almost certainly unknown to Rayna, volunteers to track her. (She was a top trainee agent, albeit over ten years ago.) When her boss, Elaine Crocker (Allison Janney), reluctantly agrees, the ultra macho Ford quits in disgust.
With her best friend Nancy (Miranda Hart) providing intelligence, Susan goes to Paris undercover. That night, Ford shows up and tells Susan she will fail because of her inexperience. The next morning, Susan discovers that De Luca’s office has burned down. She finds a photo of a man standing next to the fire. Ford appears, argues with Susan again and leaves. Susan sees the man in the photo follow him and switch his backpack with another one containing a bomb while Ford is distracted. Susan warns Ford in time and pursues the man into an abandoned building. During the ensuing fight, he falls to his death. When she checks the man’s video camera, Susan learns that De Luca is going to Rome.
In Rome, Susan meets her contact Aldo (Peter Serafinowicz). She follows Sergio into a casino, where she saves Rayna’s life. Rayna brings Susan into her inner circle and takes Susan on her private plane to Budapest. In mid-flight, the steward kills Rayna’s bodyguard and pilots, but Susan subdues him. Rayna believes Susan to be a CIA agent, but Susan convinces her that she was hired by Boyanov to protect his daughter.