Having defeated the rival gangs of Stilwater at the end of Saints Row 2 and overthrown the influence of the Ultor Corporation, the Saints have found themselves with free control of the city. They target a bank, attempting to airlift the vault out of it, but the plan goes wrong, and the Saints are incarcerated. In prison, they learn about how an international crime agency called the Syndicate, led by Phillipe Loren, has taken over many of the banks (including the one the Saints struck) and bribed the Stilwater police force. Loren smuggles the Saints' leader (the player-character), Johnny Gat, and Shaundi out of jail and onto his private jet. While in-flight, he tells them they will be allowed to live if they turn over two-thirds of their territory. The leader of the Saints rejects this offer, and a gunfight breaks out; ultimately, the player-character and Shaundi fall out the cargo hold of the plane, recover parachutes, and land safely. There is no mention if Gat makes it out alive or not.
With the Syndicate in full control of Stilwater, the Saints relocate themselves to the city of Steelport. Steelport is a city that was created as factories flourished with little city planning, and since has suffered from economic failure, contrasting the glamour of Stilwater. The Syndicate has already begun to take control of some parts of Steelport, focusing on vices like gambling and prostitution. To extend their reach, the Syndicate had divided their control of the city through three gangs. The Morning Star, lead by Loren directly, are typically European men with impeccable taste, selling guns and handling the prostitution rings. The Mexican wrestler Killbane controls the Luchadores who deal with selling drugs and gambling. The Deckers, led by hacktivist Matt Miller, are computer geniuses, and handle the money laundering. The Saints see the opportunity to take control of Steelport from these groups, and engage them to start to take control of the downtrodden city. As the gang war intensifies, a fourth group, the Special Tactical Anti-Gang (STAG) units from the government will attempt to halt any gang activity whether it be the Saints or the Syndicate.
In previous Saints Row games, the player would be able to approach each of the three rival gangs along separate storylines that ultimately culminated into a final conclusion. In The Third, the storylines between the three gangs are interconnected, and decisions that the player makes in dealing with one faction may alter the behavior of the other factions towards the player or missions that may be available later. The developers have focused on developing an open-ended storyline; the majority of storyline missions can be completed in multiple ways, and the decisions that the player makes on these missions will ultimately affect the game's ending.