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During an FBI SWAT raid of a hideout occupied by suspected Mexican drug cartel kidnappers in Chandler, Arizona, Agent Kate Macer (Emily Blunt), her partner Reggie Wayne (Daniel Kaluuya), and their team discover dozens of corpses. While the team investigates, a booby trap detonates, killing two officers. In the aftermath, Kate's boss, Dave Jennings (Victor Garber), recommends her for a task force assembled by the Department of Defense and CIA agent Matt Graver (Josh Brolin) to implicate those responsible, including Sonora Cartel lieutenant Manuel Díaz (Bernardo P. Saracino).
On the plane to El Paso, Texas, Kate meets Matt's enigmatic partner, Alejandro Gillick (Benicio del Toro). Joined by U.S. Marshalsand a team of Delta Force operatives, they embark on an operation in Juárez, Chihuahua, Mexico, to extradite one of Diaz's top men: his brother Guillermo (Edgar Arreola). While crossing back into the United States over the Bridge of the Americas, cartel members make a rescue attempt on Guillermo, only to be swiftly killed by the escort team. They return to El Paso, where Matt and Alejandro torture Guillermo and learn of a tunnel used by Díaz to ferry drugs into the U.S.
At a Border Patrol station in Arizona, Alejandro questions a group of Mexican illegal immigrants for information. Reggie and Kate confront Alejandro and Matt for more details about their mission; it is revealed that their objective is to disrupt Díaz's drug operations so that he will be called back to Mexico and lead the team to his boss: Sonora Cartel drug lord Fausto Alarcón (Julio Cedillo). The team finds the tunnel and at a bank used by Díaz's money launderers, Kate gathers records and tells Jennings that they constitute probable cause but Jennings sides with the officials who outrank him and overrules her.
At a bar, Reggie introduces Kate to Ted, a friend and local Arizona cop. While preparing to have sex at her apartment, Kate discovers a rubber wristband in Ted's possession — the same type used to bundle Díaz's laundered money. Ted tries to strangle her, sensing she knows he is corrupt. She is saved by Alejandro, who has kept a close eye on her since the bank incident, knowing the cartel would send someone after her. Alejandro and Matt threaten the lives of Ted and his family, forcing him to reveal the names of other corrupt local cops working for Díaz.
The next morning, Matt and his team prepare to follow Díaz, who has finally been called back to Alarcón. Kate protests that the FBI has no jurisdiction in Mexico and she and Reggie are dismissed, having been on the team solely to give the CIA legal permission to operate within U.S. borders. Kate insists on remaining. The team's raid on the tunnel allows Alejandro to sneak through to the Mexican side; once there, he kidnaps one of Díaz's mules, a corrupt Mexican police officer named Silvio (Maximiliano Hernández). Kate follows and attempts to arrest Alejandro, who shoots her in her bulletproof vest and tells her to go back and then forces Silvio to pursue Díaz in his police car. Kate demands answers from Matt, who explains that their ultimate goal is to strengthen U.S. enforcement over the drug trade by restoring the Medellín Cartel as a sole power; Alejandro had been hired to assassinate Alarcón and also wants revenge for his murdered wife and daughter.
Alejandro, with Silvio driving and remote help from the CIA, stops Díaz's Mercedes, after which Alejandro kills Silvio and captures Díaz. Alejandro is then driven by Díaz to Alarcón's estate, where he kills Díaz and Alarcón's guards. He then kills Alarcón's family in front of him before killing him last. The next morning, Alejandro sneaks into Kate's apartment and orders her to sign a waiver stating that the entire operation was legitimate. Kate refuses but relents after Alejandro holds her at gunpoint. After he leaves, Kate goes to her balcony, points her gun at him and hesitates. He turns around but then continues to walk when she does not shoot.