At the end of Saints Row the city of Stilwater was in the hands of the 3rd Street Saints. But the main protagonist also got blown up on Mayor Alderman's yacht, putting him in a coma. So things went down from there.

Five years have passed now and the main protagonist finally wakes up from their sleep only to find themself in prison and the city of Stilwater controlled by several rival gangs, with Johnny Gat about to be put on the electric chair. With the help of Carlos, a fellow inmate, the protagonist escapes, rescues Johnny Gat and once again begins to reform the gang and move the 3rd Street Saints back up to number 1.

Before the player can enter the open and non-linear environment of the city, they need to define who the main protagonist is by using an extensive character creator which allows for changing everything from gender to the size of the characters ears and the voice acting. But that's not the limit of customization in Saints Row 2. In shops scattered all around the city the player can buy additional clothing from underwear to hats to not only change their appearance but also the gang's. These clothes are then also available in the up to six cribs the player can unlock and buy during the course of the game. Besides changing their appearance, the player can also stash weapons and cash there, withdraw the daily earnings, rewatch cutscenes and more. They can also change the overall style of the crib and buy new stuff like a TV-set which grants them additional style points.

Style and Respect are the most important currencies besides money in the city. While respect is used to unlock missions and progress through the storyline, the player's style affects the overall respect modifier increasing the amount of respect earned. As stated, style points are earned by upgrading the characters look, home or car. Respect points are instead earned through the many activities and diversions available in the city.

Activities are mini-games that are started at a one of two specific points in the game world and span out over six difficulty levels. After completing three levels, the player gains unlockables like a 5% discount on clothes. Besides activities already known from Saints Row, Saints Row 2 includes six new ones including "Crowd Control" in which the player needs to protect a VIP from intrusive fans and "FUZZ", a parody of COPS in which the player is followed by a camera crew and has to deal with criminals in a very creative manner to gain points. Diversions on the other hand include the simple driving on the wrong side of the road, doing stunts, playing poker in a casino, hijacking a car with more than one person in it and taking the passengers hostage and doing the job side-missions like driving the tow-truck or playing taxi.

The game also features several multiplayer modes ranging from a two-person coop-mode to twelve player deathmatch ("Gangsta Brawl") and team-deathmatch ("Team Gangsta Brawl") and a mode called "Strong Arm" in which the team wins that manages to earn $100,000 first. This is accomplished by winning events based on single player activities like racing. Each activity has a time limit and at the end the winner goes home with $10,000.