After the McManus brothers, Connor and Murphy, and their father, Noah (a.k.a. "Il Duce"), assassinated Joe Yakavetta, they fled to Ireland. Eight years later, their uncle Father Sibeal arrives to inform them that a renowned Boston priest was murdered by a mysterious assassin who attempted to frame the Saints by using their ritual assassination style. In response, the brothers dig up their old gear and weapons and depart for the United States.
En route to Boston aboard a container ship, the brothers meet a Mexican underground fighter named Romeo, who recognizes them as the Saints. Romeo convinces them to let him join them as their new partner. Hearing a radio broadcast regarding Joe's son, Concezio Yakavetta, they deduce that he must have hired the hit-man who killed the priest in order to draw them out of hiding.
Meanwhile, Detectives Greenly, Dolly and Duffy are at the scene of the priest's murder. They are greeted by Special Agent Eunice Bloom, the protĂŠgĂŠe of Paul Smecker (who has died) who has been assigned to investigate the murder and determine whether or not the Saints are responsible. She comes to the conclusion that it was not the Saints who murdered the cleric and begins an investigation to find the real assassin. She and the other officers find out the assassin is Ottilio Panza, a man who appears to be working for a mysterious man known only as "The Old Man".
Connor, Murphy and Romeo hit a warehouse that is being used by an Asian gang to process heroin for Yakavetta. After killing everyone at the warehouse, Connor and Murphy reunite with their old bartender friend, Doc. They learn that the assassin was an independent contractor and that Yakavetta himself is hiding in the Prudential Tower. Later at the warehouse, now a crime scene, Bloom confirms that the Saints have returned. Bloom interrupts a massage in progress and hits a mob boss with a paddle, displaying her identity.
The brothers and Romeo have one of Yakavetta's underbosses named Gorgeous George set up a meeting with a group of mobsters at a bar, where they kill them. Panza arrives shortly after and attempts to ambush the brothers, but Bloom arrives in time to save them by wounding Panza who flees. Bloom introduces herself, revealing her intentions to help the Saints in Smecker's place. The group then cleans up the crime scene to make it look as if the mobsters had turned on each other. Later, Bloom reunites the other detectives with the Saints, thus bringing them in on their plans.
Yakavetta calls a meeting with his crew, during which the Saints arrive and kill everyone including Yakavetta. Bloom interrogates Yakavetta's Consigliere Jimmy and learns of the Old Man's involvement with Panza. The crime scene is visited by FBI Special Agent Kuntsler, who takes over the gang murder case upon suspending Bloom. Later at the bar, Greenly arrives to celebrate the boys' victory, but is shot and killed by Panza. Noah, earlier having decided to help his sons, unexpectedly arrives to demand Panza tell him the Old Man's location. They engage in a type of "Russian Roulette" stand-off and after Panza still refuses to answer, Noah kills him.
Noah reveals to the group that in 1958 New York, he watched a trio of mobsters brutally murder his father in front of his eyes. Consumed with anger and wanting revenge, Noah killed the mobsters with the help of his best friend Louie, who is revealed to be the Old Man. Noah still felt unsatisfied, so Louie helped him pick out mobsters to kill. They continued this until 1975, when Louie gave Noah up to the police.
Bloom illegally obtains a file regarding Louie's location and gives it to Noah. Louie, anticipating the Saints arrival at his mansion, has several hit-men stationed on the grounds. When the McManus family arrives, Louie reveals that he had only used Noah to eliminate the competition in the Mafia, afterwards giving him up to the police when he was no longer useful. After this however, the Mafia cast Louie himself out for the very same reason. He then helped rebuild the Yakavetta family after Joe's demise and let the Saints take out the rest of the organization so Louie could take control. Louie signals the hit-men waiting to take out the Saints to make their move, but the Saints kill them all. Noah suffers a fatal gunshot wound, but kills Louie before he dies. The Police arrive and arrest the wounded Connor, Murphy and Romeo.
Bloom meets with Father Sibeal who has arranged to take her to a safe place out of the country to flee FBI prosecution. She is shocked to discover that Sibeal has been working with Smecker who faked his own death and developed a network of support for the Saints and their work. Smecker tells Bloom his plans to break the Saints out of prison.
As protesters outside of the prison shout for the freedom of the Saints, Connor and Murphy stare out of their window at the sea of prisoners in the yard, finding that they'll have plenty of work while they wait to be freed.

Question: Who killed Yakavetta?
Answer: The Saints
Alternative answer: the Saints