Chris Farraday (Mark Wahlberg) is an ex-smuggler who now has a peaceful life with his wife, Kate (Kate Beckinsale), and their two sons in New Orleans. They learn that Kate's brother Andy (Caleb Landry Jones) was smuggling drugs, but dropped them into the Mississippi River during a surprise inspection by U.S. Customs and Border Protection.
Andy's boss, mobster Tim Briggs (Giovanni Ribisi), threatens to kill Chris' family if Andy doesn't pay him back $700,000. Chris decides to raise the money by running contraband, working with his former smuggling partner, Sebastian Abney (Ben Foster), who now owns a legitimate construction company. Promising Kate he will not run drugs, Chris joins a cargo ship, planning to buy $10,000,000 in fake bills in Panama and smuggle them into the U.S. He is joined by Andy, his good friend Danny Raymer (Lukas Haas), and gets help from crew mates. After Briggs breaks into Chris' house and intimidates his wife and children, Kate moves into Sebastian's house for safety.
In Panama, Chris discovers that the only one who can provide high quality fake bills is crime lord Gonzalo (Diego Luna). Leaving Andy in the van with the money for the fake bills, Chris meets with Gonzalo to negotiate. Briggs calls Andy, threatens to kill one of Chris' sons and forces him to take the money and buy cocaine. With the money gone, Chris and Danny agree to help Gonzalo rob an armored car in exchange for the fake bills. After a shootout in which Gonzalo's group along with numerous police and security officers get killed, they successfully steal a Jackson Pollock painting that resembles a splattered tarp. Chris and Danny barely make it back to the ship with the fake bills and the painting. They drive the van with contraband into a container, which is loaded onto their cargo ship. Chris hits and berates Andy for using the money to buy cocaine, but apologizes when Andy explains the reason.
It is revealed that Sebastian is working with Briggs, and he desperately needs money to pay gangster Jim Church (David O'Hara). Sebastian calls Chris and learns that Chris plans to get rid of the cocaine Andy bought. Sebastian instructs Briggs to threaten Kate. Through Kate, Briggs warns Chris not to dump the cocaine. Chris realizes that Sebastian has betrayed him. Sebastian contacts the cargo ship's Captain Camp (J. K. Simmons), with whom he has a partnership. He tells Camp of Chris' smuggled contraband, and promises him a share if he secures it. Unable to get Chris to give up the contraband, Camp calls U.S. Customs to inspect the ship in New Orleans. The Customs agents find the container with Chris' van, which is empty except for the paint splattered tarp, which they ignore.
Once Chris is on shore, Briggs and his thugs demand the drug package. Chris takes Briggs to Camp's house, having made a duplicate key while on the ship, and knowingly activates the security system. Chris opens Camp's carpet cleaner and retrieves the cocaine from it. While Briggs and his gang sit in Camp's living room with the cocaine, Chris sneaks out. Camp awakens to the noise and comes into the living room as the police arrive. Both Briggs's group and Camp are arrested for possession of the cocaine.
Warned by Chris, Kate leaves Sebastian's house. When she goes back to retrieve some personal items, Sebastian gets angry with her and accidentally pushes her against a bathtub. Thinking she is dead, he dumps her (unconscious) body in a yet to be poured foundation at one of his construction sites. Chris goes to Sebastian's construction site and manages to locate and save Kate by calling her cellphone. Sebastian is arrested and sent to prison, where he is greeted by a lynch mob.
Danny retrieves the fake bills, which were dumped into the Mississippi River by Chris before docking in New Orleans. At a U.S. Customs auction, Andy buys the escape van earlier confiscated from the cargo ship, and finds the painting still in it. Church pays Chris $3 million for the fake currency and asks about the missing Jackson Pollock. Chris learns the painting can be fenced for over $20 million on the black market. The film ends with Chris, Kate, Andy and the boys beginning a new life in a waterfront house.