Susan Cooper, portrayed by Melissa McCarthy, is a CIA analyst bound to her desk, tasked with guiding her partner, Agent Bradley Fine, played by Jude Law, on a crucial mission to Varna. As Fine attempts to track down a suitcase nuke, he mistakenly kills Tihomir Boyanov after he sneezes, failing to uncover the nuke's location, which is solely known to Boyanov. The situation escalates when the agency discovers that Boyanov’s daughter, Rayna, portrayed by Rose Byrne, may hold the key to the device’s whereabouts. In a twist of fate, Rayna unexpectedly shoots Fine dead while Susan covertly watches the incident online. Aware of the identities of all the top agents, including Fine and Rick Ford, played by Jason Statham, Rayna poses a significant threat. Despite being unknown to Rayna, Susan bravely volunteers to go undercover in the field, and her superior, Elaine Crocker, portrayed by Allison Janney, approves her involvement. Ford, however, is enraged that Susan has been selected.
Now in Paris, Susan shadows Sergio De Luca, a character played by Bobby Cannavale. Her analytical skills helped pinpoint his number on a piece of paper found at the scene of Fine's demise, leading the CIA to believe that Rayna intends to use De Luca to broker a deal for the tactical nuke. One night, Ford visits Susan at her hotel, adamantly stating that her lack of experience will jeopardize the mission. The following day, she recognizes an assassin associated with De Luca in the hotel, witnessing a critical exchange of bags—one containing a bomb. Acting quickly, she warns Ford, who discards the bag just before it detonates, and as Susan confronts the assassin in a skirmish, he is ultimately killed. In the ensuing chaos, she recovers crucial footage hinting at De Luca's plans to travel to Rome to negotiate the sale of the nuke.
In Rome, Susan connects with her CIA contact, Aldo, played by Peter Serafinowicz, who, with his suave demeanor, makes unwelcome advances toward her while assisting in tracking De Luca. Her mission leads her to a casino where she unexpectedly crosses paths with Rayna, ultimately saving her from an assassination attempt and infiltrating her inner circle. During their flight to Budapest aboard Rayna's private jet, the situation spirals out of control when a steward turns rogue, attempting to take down both Rayna and Susan. In a show of bravery, Susan manages to outmaneuver and subdued the assailant, emergency landing the plane in Budapest.
Under the assumption that Susan is a CIA agent, Rayna believes in Susan's lie that she has been assigned as her bodyguard. In Budapest, they reunite with Susan's best friend, Nancy B. Artingstall, portrayed by Miranda Hart, who has come to provide vital backup. After a sudden attack on their lives, Susan instructs Nancy to protect Rayna while she pursues the shooter. This villain turns out to be Karen Walker, a double agent working for the CIA who betrayed Rayna. Just as Walker prepares to strike, she is taken out by a mysterious sniper, further complicating the existing chaos. With most of Rayna’s defenders eliminated, she insists on reinforcing her security, bringing Aldo into the fold.
Later that evening, Susan, Nancy, and Rayna attend a gathering where they are introduced to Lia, De Luca's highly dangerous associate. In a tense showdown, Nancy creates a diversion, allowing Susan to confront Lia, a skilled assassin in her own right. Just as Susan is on the brink of apprehending Lia, she is unexpectedly stabbed in the chest by an unidentified assailant—who shocking turns out to be Bradley Fine, alive and well. Fine confesses that he faked his death in order to build trust with Rayna and gather intelligence on the nuke's location, also revealing to Susan that he was responsible for the assassination of Karen.
With their lives hanging in the balance, Susan and Aldo find a way to escape captivity and plot to bring down De Luca from the inside as they attend a deal at his mansion. In a high-stakes moment, Chechen terrorist Solsa Dudaev and his men arrive to negotiate the acquisition of the nuke for a suitcase filled with diamonds. As Rayna reveals critical information about the nuke's location, De Luca, sensing a threat, kills Dudaev and his crew, showcasing his ruthless nature. In a tense standoff, just when it seems that Rayna's life is doomed, Ford returns, providing a distraction that allows Susan to once again save Rayna.
De Luca, now in possession of the device and diamonds, attempts an escape via helicopter, leading to a perilous situation where Susan and Ford cling to the landing gear. In a fierce struggle, Ford falls into the lake, leaving Susan to confront De Luca alone. With help from Nancy and Aldo in a rescue helicopter, Susan defeats De Luca and secures the device. As a consequence of the chaos, Rayna is arrested, yet a bond seems to form between her and Susan, suggesting a burgeoning friendship. Aldo later reveals his true identity as an MI6 agent, inviting Susan to dinner should their paths intersect in London, an offer she graciously accepts. Meanwhile, she turns down a similar opportunity from Fine and instead chooses a fun girls' night out with Nancy. However, the morning after, she wakes amid a mess of empty champagne bottles, screaming in shock as the realization hits her that she has spent the night with Ford.
