The Prologue features three crooks - Michael Townley, Trevor Phillips and Brad Snyder - robbing a cash depot up in the town of Ludendorff. The robbery goes really wrong near the end, when both Michael and Brad are shot by an FIB sniper as they make their getaway. Trevor reluctantly abandons the two and disappears into the wilderness. Brad is arrested and incarcerated, and Michael seemingly dies, but is later revealed to have faked his death.
Nine years later, Michael - now with a new identity and the last name of "De Santa" - is living in a fancy mansion up in Vinewood Hills, Los Santos, deeply unsatisfied with his life and his Dysfunctional Family; generally unhappily wife Amanda, lazy manchild son Jimmy, and bratty and attention hungry daughter Tracey.
Michael later meets Franklin Clinton, a gangbanger working for crooked car dealer Simeon Yetarian, when the latter breaks into the house to repossess an overly expensive car Simeon had sold Jimmy. After this incident, Michael takes a shine to the younger man, who wishes to leave the gangbanger lifestyle and make it big, a sentiment encouraged by the reckless and life-threatening stupidity of his best friend and fellow gangbanger Lamar Davis. The two of them eventually team up to go after a tennis coach whom Amanda was having an affair with, but while doing so they destroy a valuable mansion belonging to a mistress of Mexican drug lord Martin Madrazo, who demands that Michael pay him $2,500,000 in compensation.
To raise the money, Michael and Franklin rob a jewellery store with the help of criminal strategist Lester Crest, an old associate of Michael's. They succeed in paying off the debt, but as a result of the robbery, Trevor - who has been operating as a meth dealer within the desert town of Sandy Shores since the failed North Yankton job - discovers that Michael is still alive. After settling his affairs in Sandy Shores, including wiping out the Aztecas gang and two chapters of The Lost MC - killing Johnny Klebitz, Terry and Clay in the process - and unsuccessfully trying to set up a partnership with the Los Santos Triads, he travels to Los Santos to confront Michael, none too happy with the guy for ditching him and Brad nine years ago. In addition to him, Michael is contacted by corrupt FIB agents Dave Norton - the guy who "shot him" and helped him fake his death all those years ago - and Steve Haines, who force the three protagonists to participate in a number of jobs aimed at undermining the FIB's rival, the IAA.
Alongside their work with the FIB, each of the protagonists has their own struggles to deal with. Franklin begins assassinating corrupt businesspeople for Lester, and discovers that fellow gangbanger Stretch is trying to betray him and Lamar to rival gang the Ballas, but Lamar refuses to heed his friend's warnings. Trevor establishes himself in Los Santos and carries out a number of robberies on Merryweather Security, a private security firm with permission to operate on US soil. Michael's relations with his family collapse and they all leave him, but one of the FIB jobs results in him being introduced to billionaire venture capitalist and Merryweather co-owner Devin Weston, who arranges to have Michael work with movie producer Solomon Richards, Michael's personal idol. As part of the aforementioned agreement, Devin hires Franklin and Lamar to steal a series of high-end cars for him, but holds out on paying them when the job is completed.
Michael and Trevor are later hired by Madrazo to assassinate one of the drug lord's nephews before he can testify against his uncle, but after Madrazo stiffs them on payment, Trevor responds by kidnapping Madrazo's wife Patricia, forcing the pair to flee Los Santos for their own safety. Michael steals an Aztec statue in order to placate Madrazo, and placates Trevor by proposing to rob the Union Depository, a "super bank" that holds America's gold reserves. Trevor later returns Patricia - despite the two of them growing close - to Madrazo, and intimidates the drug lord into being a better husband.
Later on, Trevor visits Michael to try and convince him to return to the life of a criminal, but Michael, happy to make movies with Solomon, instead recommits to his family. As the conversation continues, Trevor becomes suspicious about Brad's fate, and travels to North Yankton to find out the truth. Despite Michael attempting to convince him to give up, Trevor discovers that Brad was killed nine years ago, and buried in the grave meant for Michael, who had tried to betray the two in order to get out of the criminal world and protect his family. Enraged at the betrayal, Trevor arranges for Michael to be captured by the Triads, who had mistaken Michael for Trevor's boyfriend. Franklin later rescues Michael from being killed by the Triads after Trevor refuses to do so.
The FIB missions come to a close when Haines coerces Michael and Franklin into breaking into the FIB building to destroy incriminating evidence against him, in exchange for the evidence against Michael also being destroyed. Michael later meets up with Dave and Steve to conclude their agreement, only for Haines to attempt to arrest Michael and Dave to cover up his involvement in the break-in. What follows is an increasingly chaotic mexican standoff as the IAA, thr FIB and Merryweather all show up on the scene, which directly leads into the mother of all GTA shootouts taking place. Trevor unexpectedly shows up to save Michael, not wanting to lose the opportunity to kill the guy, and the two of them grudgingly agree to rob the Union Depository together before going their separate ways.
Not long afterwards, the three protagonists reluctantly work together to rescue Lamar - who has been betrayed by Stretch once again - but after the job, Franklin is contacted by Haines and Norton and ordered to kill Trevor, whom they feel is too much of a loose cannon. Around this time, Michael - now an associate producer for Solomon - and his family begin to reconcile with one another, with Michael also feeling a lot better for his job with Solomon. Shortly after the two of them finish their first film, Devin attempts to have the master copy of it destroyed in order to claim the insurance money from it. Michael interferes, and in the resulting chaos, Devin's attorney is killed, prompting Devin to send a Merryweather hit squad after Michael's family. Michael dispatches them, and proposes to Lester that they do the Union Depository job as soon as possible
The protagonists pull off the robbery, stealing around $200,000,000 worth of gold. Shortly after the robbery however, Devin pays Franklin a visit and instructs him to kill Michael for all the trouble he's caused Devin, warning Franklin that Michael has betrayed everyone he's ever worked with. With this, and the FIB's instructions to kill Trevor, Franklin is at a moral crossroads.
If Franklin decides to kill Trevor, he and Michael work together to do so before going their seperate ways, and Haines gets Weston off his back before warning Franklin not to contact him again. If Franklin decides to kill Michael, Devin gets the FIB off his back before smugly declaring that he has no further use for Franklin, who is also rejected by both Michael's family and Trevor for his betrayal.
Alternatively, in what's implied by some artwork and a few scenes in the trailer to be the true endingnote , Frank can Take a Third Option and call Lester for help. Lester proposes that the protagonists lure the FIB and Merryweather into an ambush at the foundry being used to melt down the gold from the Union Depository job. After withstanding a massive assault from both the FIB and Merryweather, the protagonists proceed to wipe out all their enemies; Trevor kills Haines, Franklin kills Wei Cheng and Micheal kills Stretch, before Trevor kidnaps Devin and locks him in the trunk of his own car, driving him away to Blaine County. The protagonists take a moment to gloat before pushing the car off a cliff, killing Devin. They stop working together and carry on with their lives, but still remain friends.