Five years later, the Boss has been elected President of the United States, with several members of the Saints acting as cabinet. While preparing for a press conference, the Boss is told that Asha and Matt have arrived at the White House, which the Saints have renamed the White Crib, to warn them of what they suspect is an impending alien invasion. Just as the Boss is informed, the invasion begins, spearheaded by the alien warlord Zinyak, who captures all of the cabinet members as well as the Boss.
The Boss wakes in what appears to be a 50s sitcom set in the city of Steelport, devoid of violence or foul language. The Saints' computer specialist, Kinzie Kensington, contacts the Boss and informs them that they are trapped inside a simulation, and that each of the Zin's prisoners are trapped in personal simulations of their own fears in order to break their will, as the Boss fears of a world devoid of foul language and violence. With Kinzie's help, the Boss breaks free of the simulation and joins Kinzie and Vice President Keith David in a stolen Zin ship. While the trio attempt to contact reinforcements from Earth, Zinyak atomizes the planet, killing everyone not already captured by the Zin. Determined to get revenge for Earth, the Boss returns to the Steelport simulation, hoping to use it to find the remaining Saints and somehow reach Zinyak. The Boss begins to go into the other Saint's simulations in order to rescue them, revealing each of their own fears including Matt's fear of being trapped in the cyberworld and Killbane coming after him, Shaundi's fear of her former calm and fun-loving self, Pierce's fear of the Saint's image turning on him, and Benjamin King's fear of his former gang the Vice Kings.
As the simulation begins to weaken under the Saints' influence, Zinyak floods virtual Steelport with copies of gang members the Boss has faced in the past. Kinzie determines that the copies are being made from someone's memory, leading the Boss to conclude that Saints lieutenant Johnny Gat, who was thought dead, is still alive and trapped within the simulation. Despite protests from Kinzie and Matt that rescuing Johnny will reveal their location to Zinyak, the Saints make their way to where Johnny is being held, while taking note of how many people are being held on Zinyak's ship implying that there may still be hope for humanity. The Boss eventually frees Johnny's mind from his nightmare of Aisha's death that he had been trapped in and gets him back to the ship. Johnny explains that during the fight in which he was presumed killed, he was actually abducted by Zinyak years in advance of their invasion, as Zinyak had concluded that Johnny could have single-handedly stopped him if left on Earth.
The Saints rally inside the simulation in order to prepare to confront Zinyak, but they are ambushed by an enormous Zin force. As they escape, Kinzie is captured by Zinyak, and the Boss emerges from the simulation to find that Keith has knocked the other Saints out and fled, showing that he betrayed the Saints. Returning to Steelport, the Boss finds Keith has been declared president of the simulation. When confronted, Keith claims that Zinyak has the means to restore Earth, and has agreed to do so in exchange for the Boss' life. The Boss, believing that Zinyak is lying, pursues Keith into his nightmare with the help of Roddy Piper, who is ultimately unable to bring himself to kill his friend and rejoins the Saints, telling them where Kinzie has been taken.
After the Boss rescues Kinzie from her nightmare, she devises a plan to crash the simulation, which will force the Zin to draw power from their ship to keep it running, thus weakening the ship itself and creating an opening for the Saints to enter. Working together, the remaining Saints manage to take control of the simulation and overload it, shutting it down just as the Boss escapes. The Boss leads an assault on Zinyak's ship, confronting him in his throne room. While the entire Zin Empire watches, Zinyak and the Boss battle each other, and with help from the Saints, the Boss kills Zinyak and emerges victorious. Impressed, the Zin forces surrender to the Boss, who becomes the new head of the Zin Empire.
The Boss asks Zinjai, one of Zinyak's servants if they truly have the technology to bring Earth back. Zinjai answers saying that they can not simply bring back Earth because of it being atomized, but mentions that the Zin have time-travel technology, which would allow the Saints to go back in time before Earth was destroyed. With this in mind, the Boss looks at the Saints and says, "Let's go on a field trip." As the credits roll, there is a curtain call set to Montell Jordan's "This Is How We Do It". In a post-credits scene, Zinjai shows the Boss the many humans in stasis that Zinyak had collected from across history, one of them being the nineteenth century writer, Jane Austen. Being a fan of Austen, the Boss wakes her out of stasis, revealing that she had been the narrator throughout the game.
There is also a non-canonical "bad ending" that plays out should the player not complete all of the loyalty missions. In this ending after the Zin forces surrender to the Boss, the Saints make their plans to take over more planets, unaware of their ability to meet Austen or return to Earth.
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