Some time after Saints Row: The Third the Saints have become heroes for protecting the national monument of Steelport. They team up with MI6 on a mission in the Middle-East to apprehend Cyrus Temple former leader of Special Tactics Anti-Gang squad (STAG), having gone off the deep end when he was exiled by the U.S. after he attempted to frame the Saints for terrorism.
Temple has sided Arabian terrorists and is preparing to launch a nuke at Washington, the Saints infiltrate his hideout and the Boss confronts Temple in a scuffle and sends Temple into a furnace, before he dies he launches the nuke at Washington, the Boss rushes to disarm it mid-flight, the nuke detonates safely over Washington and the Boss lands in the Oval office.
Five years later the Boss is President of the United States and has done a poor job, fellow Saint and former FBI hacker Kinzie Kensington has been receiving warnings of a possible alien invasion but no-one believes her, until the invasion begins by a race known as Zin and their leader Zinyak. Many of the boss's cabinet are abducted as is the Boss when they engage Zinyak in a one-on-one.
The Boss awakens in a nineties-fifties sitcom called Leave it to the Saints, the Boss drives through the streets of Pleasantville, a recreation of idyllic small-town America in the fifties and stops at a meet and greet at the local diner. When a fan seemingly glitches the Boss curses in alarm and the people turn on them, the Boss flees the diner and is contacted by Kinzie who provides them with weapons to carnage, the town is a digital simulation based on the Boss's worst fears, namely a world free of mayhem. After causing enough damage Zinyak appears in holographic form in the sky and tells the Boss they're trapped in a simulated prison that can be changed on command and reshapes the landscape into an alternate Steelport.
The Boss looks for a way out with Kinzie's help and is eventually freed from the simulation, they wake up in a preservation pod on board a Zin ship and is rescued by Kinzie and the Vice President Keith David, Zinyak fires a laser at the Earth killing everyone who wasn't captured and trapping the Saints in space. The Boss turns to rescuing the rest of their cabinet, starting with former Steelport Syndicate hacker and MI6 tech Matt Miller. Then Shaundi is found in a simulation of the Syndicate airplane where Johnny Gat was presumed dead. Other prisoners are Pierce Washington, Lieutenant and face of the Saints, Asha Odekar, MI6 agent and Chief of Staff and former Vice Kings boss Benjamin King. Eventually the Boss discovers a simulation based on the nightmares of Johnny Gat and discovers Gat is alive.
The Boss enters Gat's simulation where the Gat's nightmare is reliving the death of his girlfriend Aisha. Gat is rescued having single-handedly slaughtered Zin troops. The truth behind his assumed death is revealed, the Syndicate didn't kill him but rather Gat fought valiantly until Zinyak appeared and took him prisoner, believing Gat alone could've stopped the Zin invasion.
While inside the simulation the crew are attacked by a Zin battalion, the attack is averted but Kinzie is captured. Back on the Zin ship the Zin are attacking, King and Washington are unconscious, Miller, Odekar and David are missing, suspicion falls on the MI6 agents until they are found unconscious too. Keith David has betrayed the Saints.
David has taken over the simulated Steelport as President and the Boss confronts him, David offers the Boss's life in exchange for rebuilding Earth, the Boss chases David through his own nightmare world, a recreation of They Live, particularly the back alley brawl with Rowdy Roddy Piper. The Boss helps Piper defeat David and he comes to his senses, rejoining the Saints and giving Kinzie's location.
Kinzie is found in the same fifties town the Boss was in, she is the wife of Cyrus Temple, she's rescued and threatens the Boss not to tell of her nightmare world. The Saints invade the simulation damaging its cyber security, and finally taking the fight to Zinyak the Boss dons a power armor, defeats Zinyak in one-on-one and is made the new Zin emperor.
There are two endings depending on whether the other character's loyalty missions were completed.
Good ending: The Boss asks Zinyak's personal servant if Earth can be restored, it cannot for it was atomized, but the Zin have time-travel technology, Zinyak used to abduct his favorite historical figures and kept them in stasis pods, the Boss searches these pods and finds an idol of theirs, Jane Austen.
Bad ending: The Boss takes the ship to conquer another planet not knowing of the time-travel technology.