Best friends Chon and Ben are wealthy marijuana growers living in Laguna Beach, California. The two are in a polyamorous relationship with Ophelia.
The trio receive a video from Miguel "Lado" Arroyo, enforcer of the Baja Cartel. The cartel offers a partnership, but Chon and Ben offer to hand over their network and get out of the business. The cartel wants their expertise and insists on a partnership, Chon and Ben make plans with Ophelia to leave and go to Indonesia for a year, not telling her that they are fleeing from the cartel. Chon and Ben speak to corrupt DEA agent Dennis Cain who urges them to partner with the cartel. Ophelia is kidnapped by Lado's crew. Chon and Ben are notified of Ophelia's kidnapping via a video call from the cartel's leader, Elena Sánchez, who threatens to harm Ophelia before again urging the two to partner with the cartel.
Chon and Ben speak with Dennis about the situation, who informs them that Elena is facing the loss of her political connections in Mexico, thus her efforts to move into the US. She has already lost her entire family, with the exception of her daughter, Magda. Dennis provides DEA intel so Ben and Chon can retaliate against Elena. With help from Chon's Navy SEAL friends, the duo attacks a cartel truck, killing seven of Elena's men. Elena, traveling to the US to visit her daughter and deal with the escalating situation, has Ophelia brought with her. The duo decides to frame Alex, a high-ranking member of the cartel, for the murders. With help from Dennis, they falsify the evidence and give it to Lado, who tortures Alex before forcing Ben to immolate him. During the torture, Elena forces Ophelia to watch as a view of her power. While being tortured, the man begs for his life "on Magda", revealing to Chon and Ben that Elena's daughter is still alive. They kidnap Magda and video-call Elena to establish that they are now in control.
With Elena at their mercy, they arrange a desert meeting to exchange Ophelia and Magda at which snipers from both sides are in position. Elena asks who revealed her daughter's location, and Chon tells her it was Lado. She tries to kill Lado, but he shoots her first; a firefight erupts, and Chon is shot several times. Lado is shot in the back by Ben, but shoots him in the neck before Ophelia kills him. Ben is mortally wounded, and Chon injects him, Ophelia and himself with a fatal overdose so they can die together. This is the believed end of the film...
....until Ophelia reveals it to be a dream. At the meeting, Lado steals Elena's car and escapes as Dennis leads DEA agents to the scene. Everyone but Lado and Magda are arrested. Because Ben has incriminating information about Dennis, Dennis identifies Ben and Chon as his informants in the cartel and they are released. Elena is sentenced to thirty years in prison, and El Azul and Lado create a new cartel called the Azulados.
- Salma Hayek also portrayed Santánico Pandemonium in the 1996 film From Dusk Till Dawn.