After the happenings of Saints Row: The Third, the Saints gang extended their reach and the protagonist became the President of the USA. Unfortunately during a press conference, disaster happens: aliens attack the White House, kidnap the Saints and trap each in their personal, indefinitely looping nightmare. Fortunately Kinzie, the group's hacker, rescues the protagonist and together they flee into a space ship with the goal to rescue the rest of the gang. The majority of the game it spent in an open world simulation of Steelport, the location of Saints Row: The Third. There is an extensive character creation which allows to tune every aspect of the protagonist's look and the choice between seven voices (three male, three female and Nolan North).

Saints Row IV continues the course of its predecessor into over-the-top action and humour. The twist of this game is that the protagonist receives super powers within the simulation, e.g. super jump, fast running or telekinesis, which help with moving fast and killing aliens which replace cops as law enforcement. Those powers make driving practically unnecessary, but the player may still hijack and use cars. Third-person fights with melee and ranged weapons still play an important role.

Like all Saints Row games, it features various side activities which can be activated in certain points of the game world. Then the game switches to the mini game and after completing it, the player is rated with either bronze, silver or gold medal depending on the performance. While some of the games are known from the predecessors, e.g. fraud or tank mayhem, the majority are new and are designed around the superpowers. For example, there is a race in which the player needs to solve a running course as fast as possible and another one requires to jump precisely on platforms. While those mini games were an essential part of the main mission line in previous Saints Row games, this time they are only required for the team members' side quests. The main storyline features varied missions which mostly involve moving to a point and killing everything in sight, but also various sequences parodying other genres like side-scrolling brawlers or top-down shooters. Additionally there are other side activities like collecting audio diaries or destroying the aliens' infrastructure points.