Call of Juarez: The Cartel follows an undercover team tasked with investigating a bombing at an LAPD office. In the meeting room, the team is assembled, consisting of Ben McCall, an LAPD detective; Kim Evans, an FBI agent; and Eddie Guerra from DEA. They are ordered to work in secrecy, gathering evidence on possible involvement by local gangsters and the Mendoza cartel from Mexico.
The game features co-operative gameplay with three playable characters, each having unique abilities and weapons. Players can choose who to control throughout the mission, taking into account the surroundings and enemy positions. The game includes car chase sequences, shootouts, and brief combat encounters where players must breach open doors to eliminate enemies.