- Several new upstart gangs have been able to sweep in and make their mark on Stilwater. As leader of the Saints, you'll have to do whatever it takes to protect the members of your gang.
- Several new upstart gangs have been able to sweep in and make their mark on Stilwater. As leader of the Saints, you'll have to do whatever it takes to protect the members of your gang from new enemies, including the Ultor Corporation and rival gangs.—Anonymous
- Years after the Boss was supposedly killed in a assassination attempt they awaken on a prison island off the coast of Stilwater. Immediately after awakening they are approached by Carlos Mendoza, a brother of a former Third Street Saint, they escape from the prison and head back to Stilwater, where the Boss finds their old turf has been renovated by the clothing corporation Ultor, not only that, but the Saints have disbanded without a leader, and now Stilwater is under command of three new gangs, Sons of Samedi, a Haitian voodoo gang that rules the drug trade. The Ronin, a Japanese biker gang. And the Brotherhood, an outlaw anarchist gang.
The Boss starts looking for past members of the Saints, Julius has disappeared, Dex left the gang life and works in Ultor and Troy was an undercover police officer, now the chief of police. Only Johnny Gat is still active and on death row for 300+ counts of murder, the Boss breaches the courtroom where Gat is awaiting conviction and drives him home to his girlfriend Aisha, currently in hiding after the Boss helped fake her death.
New recruits are called in as lieutenants, Carlos is one such newcomer, along with Shaundi, a hippie stoner and Pierce Washington. The Boss assigns each of these lieutenants to a particular gang, mirroring Julius' speech in the previous game.
Carlos is assigned to the Brotherhood, the Boss joins him at a meet with the leader, Maero. He offers the Saints a deal of joint leadership of Stilwater, but he only offers 20%. The Boss refuses such a scant offer starting hostilities between the two gangs, the Boss attacks Maero on his turf by putting radioactive waste into his tattooing needle burning his face, the Brotherhood retaliates by subjecting Carlos to a form of keelhauling, chaining him by his feet to the back of a truck and dragging him through the streets, the Boss stops the vehicle but has to euthanize the disfigured Carlos. The Boss gets their revenge by kidnapping Maero's girlfriend Jessica and trapping her in the trunk of her car and leaving her in the path of a Maero's monster truck at a demolition derby. Further damages are made when the Boss attacks Matt, Maero's tattooist and member of the Feed Dogs, a punk band during a concert, then burns his arm on a pyrotechnic. Maero confronts Ultor CEO Dane Vogel and demands the release of Brotherhood members from prison, the Boss intercepts the prison buses, destroying them all. Maero has lost his backup and his shipment of munitions which Ultor seized as payment. The Boss hears of this shipment and boards a ship containing weapons to arm the Saints in the raid on Brotherhood territory. The Saints attack, Matt is killed and Maero escapes. Maero challenges the Boss to a final showdown at the Dome, the Boss kills Maero and walks away.
Shaundi and Pierce are fighting the Sons of Samedi, the first order of business is to conquer the drug business, catching the attention of their leader, the General and his bodyguard Mr Sunshine. A local DJ known as Veteran Child is the main dealer of their supply and an old boyfriend of Shaundi, he kidnaps her and the Boss pursues and kills him. The General captures the Boss and overdoses him, the Boss still manages to escape and fight of the Sons attack on Saints territory. Mr Sunshine is fought in the drug factory and after surviving multiple gunshot wounds is decapitated. The Boss infiltrates the police station to hack the CCTV and find the General, his convoy is found and the General is killed.
The Boss and Gat steal from a Ronin casino, which is a problem for the current leader, Shogo Akuji, already a disgrace to his father Kazuo. Shogo order his lieutenant, Jyunichi to take Aisha hostage, he prepares an ambush with fellow Ronin, when Gat and the Boss return home, Aisha tries to warn Johnny and Jyunichi decapitates her. The Boss defeats many Ronin and Gat is wounded in a sword fight with Jyunichi. Gat is hospitalized, the Boss gets word of Kazuo arriving to America and searches for him at the airport, where Jyunichi has already collected him. It seems Kazuo prefers Jyunichi over Shogo, which the latter arranges to have Jyunichi killed by the Saints. Johnny is discharged from hospital and the Boss receives information of a valuable Ronin property to destroy from Dane Vogel. At Aisha's funeral Shogo makes another attempt to win his father's respect by killing Gat and the Boss at the funeral, the Ronin bikers are killed and Shogo is buried alive for his disrespect. Back at the Saints hangout the Boss receives a visit from an old business acquaintance Mr Wong, who thanks the Boss for Shogo's death. Then the Ronin attack the place, with Kazuo among them, the Ronin are defeated and Kazuo escapes. Kazuo attacks Mr Wong at a festival, which the Boss intervenes wounding Kazuo in a sword fight and leaving him to burn on a ship.
In the epilogue the Saints have reclaimed Stilwater, and now Vogel wants to further Ultor's presence in Stilwater, starting with the destruction of the Saints, the Boss fends off Ultor's private army and infiltrates a top-secret facility. Vogel is nearly fired by the board of directors and secretly hires the Boss to eliminate them and takes control for himself. The Boss attends a conference which Vogel further argues the case against the Saints, both Gat and the Boss fail to assassinate him on the spot, and the latter chases Vogel to the top of Ultor's headquarters and kills him there.
Another epilogue reveals what happened at the end of the previous game, Dex was approached by Ultor offering a job which he took, phoning Troy telling him he knew Troy was a police officer all along, but wanted clarification he'd have no problems with Dex's sudden career change. Troy calls Julius telling him to disband the Saints, he accepts but knows the new Boss would not stand down, so Julius planted the bomb that put them out of action. The Boss contacts Dex and the latter arranges a meeting at the rebuilt church in Saints Row, their former turf. Instead the Boss finds Julius there, who reveals Dex told him the same thing, Ultor soldiers surround the church and the two escape, once clear the Boss shoots Julius in the arm for his treachery, Julius regrets nothing, the Saints had become no better than the gangs they fought and the Boss owes him for saving their life back on the Row. The Boss doesn't agree as Julius also tried to kill them and shoots Julius in the head.
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