The game opens with a voiceover of a letter, addressed to a girl named Jenny, which is being written by her father, Adam 'Kane' Marcus. Kane is traveling to death row after being convicted of the manslaughter of 25 civilians in Venezuela. Another death row inmate, James Seth Lynch, hints of a mid-destination breakout unbeknownst to Kane. Their truck is involved in a head-on collision by a group of mercenaries, who set them free. Though it quickly becomes apparent that this isn't a rescue, but a kidnapping. The two are taken to a shopping mall that is under construction, where they are confronted by the four surviving members of The7. The villainous leader Elder Brother, Kane's nemesis Younger Brother, Kane's former best friend Carlos, and the silent sociopathic killer Mute. They make him an offer; retrieve what he stole from them in three weeks, or his wife and daughter will be executed. Lynch acts as a watchdog, reporting in to The7 on Kane's movements.
They want back what Kane stole from them. Kane informs to Lynch that he did not steal it, but he knows who did, and what bank they stashed it in. Using the assistance of an unnamed vaultbreaker, they manage to break into the bank. Halfway to the vault, Kane tells Lynch to secures the hostages in the lobby. Reluctently, Lynch heads upstairs while Kane and the Vaultbreaker continue to the vault. Once they access the vault, Kane immediately uses a keycode to unlock the deposit box. He retrieves one briefcase, but discovers that the second deposit box is empty. In desparation, he orders the infuriated vaultbreaker to blow open all the safety deposit boxes. Seeing that the money is not in any of the deposit boxes, Kane angrily realizes who has taken it. They make their way to the lobby to discover that Lynch has killed all the hostages in a blind rage, and the police have arrived quicker than they expected. They narrowly manage to get the escape van through, and get away from the scene. After losing the police, Kane informs Lynch that they need to go to Tokyo[3] to retrieve the last briefcase.
They head for a nightclub owned by the daughter of Retomoto, a Japanese Crime Lord. Unknownst to Lynch, Kane plans to kidnap Retomoto's daughter, Yoko, and hold her for ransom. After kidnapping Yoko, Kane reveals to Lynch who Yoko really is. This infuriates Lynch, as he claims he would have never knowingly kidnapped the daughter of a crime boss. As they escape the Tokyo nightclub, Kane and Lynch arrange a meeting with Retomoto to trade his daughter for the briefcase. Using the assistance of a pair of mercenaries known as Ryu and Shinja, Kane and Lynch proceed to a park by the Nan Lu Intersection. However, Retomoto is not there, leaving a cell phone for Kane. Retomoto, on the phone, tells Kane that he knows what The7 have done, and offers to work with Kane to get his wife and daughter back, as well as to solve the problem of The7. This infuriates Lynch, and he accidentally shoots and kills Yoko while trying to stop her getting away. Kane and the mercenaries then proceed to escape Retomoto's men and make their way to the escape van. Kane is furious with Lynch, but he soon realizes that they are out of time, and must return to The7.
Kane heads back to Los Angeles in an attempt to renegotiate with The7. Lynch questions his decision, while Kane claims that Lynch is a dead man too. Lynch denies this, and reveals that he has secretly made a deal for his survival, and even a position within The7. However, it becomes clear that The7 where simply using Lynch as a pawn. He is knocked out, and awakens to find Kane inside a shallow grave at a construction site. Kane's plea for extra time lands upon deaf ears, as The7 prepare to execute him and his family. The Brothers and Carlos depart for Havana, leaving Mute to execute Kane and his family. His wife and daughter soon arrive and confront Kane. While Kane desperately tries to talk to them, Mute shoots his wife right in front of him. Lynch, now fully conscious and infuriated, lunges at one of his captors, and in the confusion, an enraged Kane leaps out of the hole and brutally beats Mute to death with a shovel. As The7's reinforcements arrive, Kane and Lynch manage to defend Jenny from further attacks, and a large truck. After the area is clear, Kane tells Jenny to flee the scene and to continue to run no matter what.
After burying his wife by the highway, Kane decides to finish off The7 for the sake of his daughter's safety. He reluctantly allows Lynch to join his cause, after Lynch explains his own wife's murder and his supposed inability at that time to save her. With the help of the mining truck, they manage to smash through the wall of a nearby prison, inciting a riot and freeing a group of "dead men", (People who went against The7 in the past and were in turn disowned) forming their own band of ragtag convicts to wage war on The7. It is during the breaking out of Shelly, one of the convicts, that the murder of Lynch's wife is brought into doubt, with Shelly suspecting Lynch of killing his own wife, which Lynch denies.
Before flying to Havanna, Kane informs Lynch that they first need to return to Tokyo, and kill Retomoto to get the briefcase back. The crew manage to ambush and kill Retomoto at his headquarters, and retrive the missing case. They then fight through the office complex and the streets to a bus station, where the group finally manages to escape.
Days later, Kane, Lynch and their 'dead men' - Thapa, Rific and Shelly - follow The7's remaining members to Havana.[4] Kane informs Lynch that The7 reap financial benefits from assisting factions in civil wars, with Havana supposedly the last job needed for their retirement. They find themselves caught up in an ongoing civil war. Throughout the battle in the war-torn streets, Kane constantly assures the group of rewards beyond even their retirement needs. They eventually track down Carlos, who tells the group that he has been betrayed by the Brothers after the Havana operation fell apart. Thapa deserts the group abruptly, mistrusting of the promised payment and the impromptu alliance with Carlos. The remaining group fight their way through the Venezuelan Jungle[5] and drug operations, managing to locate the Brothers' base of operations. Over radio chatter, it's revealed that Jenny has been kidnapped by the Brothers and is being held hostage. Serving as a distraction, Carlos decides to detonate a mine at the entrance of the base, but is caught by soldiers, and taken to the brothers. Kane and Lynch overhear the Brothers speaking to Carlos over radio chatter and hear him being executed by the younger brother because he "shouldn't have listened to Kane". With the assistance of Rific and Shelly, Kane and Lynch manage to storm the building and find Jenny in the middle of a courtyard, which is set up as an ambush by the Brothers, who confront Kane and prepare to execute him. Though in a split second, Kane manages to shoot the mine left undetonated beside Carlos' corpse, killing the Elder Brother with the resulting explosion. However, the Younger Brother manages to escape with Jenny in the confusion.
Meanwhile, Rific and Shelly are pinned down while trying to secure the airfield. Kane and Lynch manage to hitch a ride with one of their men, and shoot down the plane before it takes off. Kane then confronts the Younger Brother in the plane as he holds Jenny hostage. Kane manages to kill the Younger Brother, and then rescues a traumatized Jenny, who hates her father for leaving his family 14 years ago, and his double-cross of The7. Rific and Shelly are desperately calling for help, but Kane takes no notice, trying his best to ignore Jenny and Lynch's pleas. At a nearby helicopter pad, the player will have to make a choice whether to save his men, or escape in the helicopter with Jenny.
In one ending, Kane and Lynch head to Rific and Shelly's position. Kane takes Jenny with him, despite Lynch's apprehensions. They are too late to save Rific, but Shelly is still alive. He feels betrayed, despite the rescue attempt. As they escape to the pier, Jenny is shot by one of the soldiers. When the adrenaline shot failed to work on her, Kane desperately carries her body along, in denial of her apparent death. Shelly loses his patience and attempts to escape on one of the boats, either escaping or dying, leaving Kane and Lynch behind. Kane and Lynch escape on the last boat, while Jenny's status is still unknown. As Lynch tells Kane to simply deal with his mistake, Kane whispers to Jenny about the letter he tried to send to her.
In another ending, Kane boards the helicopter with Jenny and leaves the remaining men, including Lynch, to 'burn'. Jenny resents her father's actions, telling him that she hates him