Note that recap pages contain unmarked spoilers.
The Playa survived the bombing and had spent the last two years in a prison hospital ward, recovering from their injuries and a coma. On the evening they regained consciousness and finally shed their bandages, the Playa meets Carlos Mendoza, the brother of a Saint. Together, the Playa and Carlos escape from prison, with Carlos explaining that while the Playa was in a coma, much and more had changed in Stilwater; Ultor, once a diminutive clothing store, had evolved into a massive business conglomerate that practically owned Stilwater, with a massive tower serving as their corporate headquarters rising from the district where the Saints were once based. As for the Saints; after the Playa's apparent death, Johnny Gat's arrest, and the subsequent arrival of new criminal groups, the Saints fell apart and dissolved.
The Playa is determined to get back to the height of their power, but Carlos suggests laying low, swapping out their prison jumpsuit for new clothes, and taking in what information they can. At a bar, the Playa learns that Gat had been arrested for an attempt on the life of Troy Bradshaw, an undercover cop who had infiltrated the Saints and since became chief of police. With over three hundred other murder convictions, Gat was on the fast track to being sentenced to the electric chair.
The Playa rushes to the courthouse and busts Gat loose, the two escaping from the authorities and taking temporary shelter in the home of Aisha, a former R&B singer and Gat's girlfriend who had been living in hiding since faking her death. Together, the Playa and Gat decide to start up the Saints again, first by finding a new base of operations: an underground hotel from Stilwater's early history once occupied by hobos until the Playa and Gat arrived to clean house. Next, they recruited new members, with the Playa personally recruiting three new lieutenants: Carlos, the same youngster who helped the Playa break out of prison; Pierce, a local gangbanger; and Shaundi, a drug enthusiast.
The Playa becomes the new Boss of the Saints, and gives assignments to their new lieutenants, tasking Carlos with scoping out the Brotherhood, Shaundi with the Sons of Samedi, and Piece, the Ronin.
Afterwards, the Boss confronts Maero's mechanic, Donny: a former member of the now defunct Westside Rollerz who tried to have the Boss killed in the past, in addition to being responsible for the death of the Boss's friend Lyn. The Boss holds Donny at gunpoint and forces him to sabotage several Brotherhood trucks. Afterwards, the Boss steals some nuclear waste from Stilwater's atomic energy plant and slips it into Maero's tattoo ink, so when Maero gets a new tattoo on his face, he ends up with horrific burn scars.
In retaliation for getting Maero's scars, his girlfriend, Jessica, has Carlos kidnapped, chained to the back of a Brotherhood truck, and keel-hauled through the streets of Stilwater while taunting the Boss over the phone. When the Boss learns of Carlos's predicament, she immediately chases down and stops the Brotherhood truck. Tragically, by then, Carlos had been so badly injured from being dragged through the streets that the Boss can do nothing else for him except end his suffering and shoot him to spare him any more pain.
Enraged at Carlos's death, the Boss jumps at the chance to get back when he learns from Shaundi that Jessica is making a deposit from the purchase of a mysterious shipment at a bank. The Boss kidnaps Jessica, tosses her into the trunk of her own car, and drives the car to an arena where Maero is holding a monster truck rally, leading to Maero unknowingly crushing his own girlfriend under his monster truck.
With Jessica dead and Donnie likely unable to help, the Boss decides to then seek out Matt, member of a local rock band and Maero's personal tattoo artist, about the shipment. To that end, she sneaks into a concert Matt is holding and interrogates Matt about the package. Matt only knows that the package is arriving by ship at the docks. For his trouble, Matt gets his hand horrifically burned by a pyrotechinics display by the Boss, ending his musical career.
Maero has the Brotherhood retaliate for Jessica's death and Matt's maiming, attacking Saints members and causing chaos throughout the streets until the Boss chases them off. All the while, Maero storms into the office of Dane Vogel, Ultor's CEO, and forces him to use his connections with the police to free any Saints that were arrested so he could deal with them himself. The Boss manages to save the Saints from being killed, though, prompting Maero to make another trip to Vogel. This time, however, Vogel has his private security force on hand to protect him. He warns Maero that he would be killed if he ever returned, and also taunts him with the fact that Ultor would be taking his shipment.
The boss later learns from Shaundi that Maero is trying to reschedule the shipment's arrival. The Boss goes to investigate and finds Ultor's security forces raiding the ship. The Boss kills the Ultor forces, takes the weapon shipment, and brings it back to the Saint's hideout.
With the Brotherhood's weapons now in their possession, the Boss rallies the Saints and prepares for a final assault on the Brotherhood. As the Saints lay siege to the Brotherhood, the Boss confronts Maero, who is wielding a minigun. The Boss manages to get the upper hand over Maero, but with the help of Matt, who sacrifices himself to hold the Boss back, and Donny waiting nearby with a getaway vehicle, Maero escapes.
Afterwards, Maero calls the Boss and demands they meet him at the Ultor Dome, alone. The Boss obliges Maero, only to find themselves confronted by Maero and the remnants of the Brotherhood, all armed to the teeth and with Maero ready to run down the Boss with his monster truck. Even with their nemesis outgunned and outnumbered, the Boss still emerges victorious, killing Maero and stamping out the Brotherhood once and for all.
Shogo Akuji, the leader of the Stilwater branch of the Ronin, tries to assure his lieutenant Jyunichi that all is fine. Unfortunately for him, his stern father, Kazuo, decides to come to get a reign on his operations. Wishing to stay in his father's good graces, Shogo orders Jyunichi to deal with the Saints.
The Saints eventually learn that Kazuo is en route to Stilwater. The Boss, in response, tends to the Ronin to thwart their attempts to attack the Saints as Vogel chastises Shogo on failing to protect Ultor's assets at Poseidon's Palace, but Shogo is confident the problem with the Saints will be remedied as Jyunichi surveils Aisha's house.
Jyunichi eventually sets up a trap in Aisha's house with other Ronin, holding Aisha hostage. When the Boss and Gat return to her house, Aisha warns them of the danger they are in, only to be cut down by Jyunichi. In a rage, Gat fights Jyunichi, but is wounded on his sword. The Boss is forced into retreat, bringing the wounded Gat to a hospital before ordering Pierce to keep an eye out for when Kazuo arrives. When the word comes in that Kazuo was flying in, the Boss and Pierce go to take him out, but Kazuo manages to arrive safely in spite of their efforts, thanks to Jyunichi.
Enraged that his father favored Jyunichi over him, Shogo anonymously calls the Boss and tips them off to Jyunichi's location in the hopes that Jyunichi would be disposed of. The Boss manages to defeat an kill Jyunichi, but Shogo's gambit, along with his vow to finish off Johnny Gat, fail to appease his father.
When the Boss visits Gat in the hospital to tell him of Jyunichi's demise, Ronin assail the hospital, forcing them to escape back to the hideout while Vogel meets with the Akujis to address the PR disaster their antics were causing. Kazuo, however, dismisses Vogel's concerns and the two cut ties, leaving the Ronin without their strongest financial connection.
While the Saints discuss their next course of action, they receive a surprise visit from Vogel, who wishes to cut off the loose ends from his now-ended relationship with the Ronin by giving the Saints the Akujis' location in the hopes that they would kill Kazuo and Shogo. According to Vogel, the Akujis were hiding in a hotel. The Boss and Pierce destroy the hotel, but the Akujis were not in the building at the time. When Kazuo and Shogo find the wreckage of the hotel, Kazuo has nothing but disdain for Shogo.
At the end of his wits, Shogo makes one last attempt on the lives of Gat and the Boss at a time when they would be most vulnerable; while attending Aisha's wedding. This attempt, however, accomplishes nothing but drawing Gat's ire. Gat warns Shogo to leave, but Shogo proceeds with his assassination attempt. When he realizes he is in over his head, Shogo attempts to escape, only to be caught by the Boss and viciously beaten by Gat. Finally, Gat empties a nearby coffin and throws Shogo inside. Shogo panics and begs to be killed quickly and mercifully, but his pleas fall on deaf ears as the Boss and Gat set about to the grim task of burying him alive.
Afterwards, the Boss reunites with one of their old friends: Mr. Wong, a Chinatown mobster allied with the Saints. Their reunion is cut short by an ambush by the Ronin, led by Kazuo himself, who is an old enemy of Mr. Wong. After fending off the Ronin, the Boss has Gat look after Wong while the Saints and Ronin fight one last time during a Chinese Heritage Festival. The Boss joins the fray and fights Kazuo on one of the junk boats at the festival, eventually gaining the upper hand and trapping Kazuo on the junk boat with his hand pinned down by a katana. The Boss informs Wong over the phone of their victory before leaving Kazuo to die on the exploding junk boat, destroying the Ronin in the process.
With the Saints proving to be an immutable obstacle, the leader of the Sons of Samedi, known only as "The General", instructs one of his underlings to deal with them: Veteran Child, DJ of a local radio station who provides drug connections between the Samedi and Stilwater. Under the threat of death, Veteran Child abducts Shaundi, one of her myriad exes. All this accomplishes is attracting the Boss's attention, who rescues Shaundi and kills Veteran Child.
After destroying some of the Samedi's drug labs, the Boss ends up meeting with the General and his lieutenant, the enigmatic Mr. Sunshine, when they are abducted in a Loa Dust smoke-filled limo. The Boss manages to escape as they learn that their hideout was being raided by the Samedi and, through a drug-fueled haze, manages to fight their way back to the hideout and drive off the Samedi.
With the streets no longer safe from the Saints, the Samedi attempt to bring in supplies by air with helicopters. Unfortunately for them, not even the skies are safe as the Boss shoots down the helicopters. Mr. Sunshine, for his failure, consents to the General's punishment of having his ear cut off. With the Samedi no longer able to manufacture Loa Dust, Mr. Sunshine attempts to rally the drug-addicted homeless of Stilwater to attack the Saints and steal their product, but the mob is repelled, after which the Boss goes to confront Mr. Sunshine at the Meat Packing District. Mr. Sunshine uses voodoo magic to fight the Boss, but bullets prove to be a more effective weapon than magic and the Boss manages to defeat him. When Mr. Sunshine keeps getting up after being shot, the Boss decides to ensure he stays dead by cutting off his head.
The Boss and Shaundi then decide to go after the General and, after raiding the police station to take their traffic monitoring equipment, track down the General's personal vehicle to the shopping mall. The General attempts to run down the Saints in a customized truck, but to no avail; the truck is destroyed, the General is dead, and the Sons of Samedi are no more.
To that end, Vogel sends Ultor's private security force, the Masako, to take out the Saints. The Boss is ambushed at a nightclub and is forced to fend for themselves as they rescue Shaundi, Pierce, and Gat.
After fending off the Masako, Shaundi tells the Boss of the "Pyramid", a secret Ultor R&D facility hidden underground. With Shaundi and Pierce running interference against Ultor, the Boss and Gat launch a raid on the Pyramid, destroying it and placing Vogel in hot water with Ultor's executives. The execs would never get the chance to do anything about Vogel, though, as the Saints receive a mysterious package informing them of a yacht party where the board of executives would be. With this information, the Saints continue their campaign of revenge against Ultor by raiding the yacht party and killing the entire board of executives, not realizing that the package had been sent by Vogel, manipulating them into helping him gain complete control over the company.
Afterwards, Vogel holds a press conference in the Saints Row district to announce the renovation of Shivington. With Vogel in the open, the Boss and Gat go to assassinate him. Vogel retreats into Ultor's headquarters, but the Boss catches up with him by commandeering an attack chopper and flying it to his office, confronting him. Vogel pleads for his life, but to no avail: the Boss shoots him once in the face and sends him falling into the streets below.
With the threat Ultor posed gone, the Boss takes their leave aboard a helicopter flown by Tobias, with Pierce and Shaundi riding with them. As Johnny Gat has the time of his life fighting off the police below, Pierce asks the Boss what they plan to do next.
"This is our city..." the Boss happily tells Pierce, "We do whatever the fuck we wanna do!"
Dex's phone number is also found in the police station. When the Boss calls him, Dex instructs the Boss to meet him at the old church where the Saints used to be based. There, the Boss doesn't find Dex: instead, they find Julius, who Dex had also called. Also present is a contingent of Masako troops: Dex had lured the Boss and Julius into a trap!
Together, Julius and the Boss fight their way out of the Masako's trap, just like old times. The good times come to an end at an empty amphitheater, however, when the Boss shoots Julius in the chest. The Boss is absolutely livid that Julius tried to have them killed, while Julius defends his actions, claiming the Saints had become no better than the gangs they had fought. Their attempt to stop the gang violence only led to the Saints taking the place of their enemies, the Julius tried to have the Boss killed two years ago to break up the gang. The Boss had learned a valuable lesson from Julius's attempt on their life, however; that it's better to take control than to simply follow the leader.
"You owe me, playa." Julius growls. "If it weren't for me, you would've died on that street corner."
"If it weren't for you, I wouldn't have been in a goddamn coma!" the Boss retorts.
"Then I guess that makes us even..." Julius sighs.
The Boss shoots Julius once more in the head before concluding: "Not really."