The story begins with 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, while Brad is seemingly arrested and incarcerated, and Michael's death is faked.
Nine years later, Michael - now with a new identity and the last name of "De Santa" - is living in a 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, attention hungry daughter Tracey. One day while chilling near Vespucci Beach, he encounters Franklin Clinton and Lamar Davis, a pair of gangbangers working as repo men for crooked car dealer Simeon Yetarian. Franklin later breaks into Michael's residence to repossess a car Simeon had sold Jimmy on expensive credit, but ends up held at gunpoint by Michael, who forces him to crash the car into Simeon's dealership before beating up the car dealer. This incident leaves Franklin out of work, and he decides to pay Michael a visit in order to get some tips on being a professional criminal, in the hope of leaving the gangbanger lifestyle behind. Though Michael insists that he's retired from that life, he takes a shine to the younger man after the two of them work together to save Jimmy from a group of boat thieves.
Michael later takes Jimmy out on a bike ride at Vespucci beach in an unsuccessful attempt to bond with him; during the trip, he earns Tracey's ire after he drags her away from a group of pornographers she's hanging out with in the hope of getting on TV. Franklin meanwhile helps Lamar kidnap a prominent member of the rival Ballas gang named "D", but they are forced to let him go after Lamar foolishly makes the ransom demand on his cellphone, allowing both the Ballas and authorities to trace it. Lamar later arranges a drug deal with D, and is accompanied to it by both Franklin and older gangbanger Harold "Stretch" Joseph, but the deal turns out to be a trap - D having not forgiven the earlier kidnapping - and the trio are forced to shoot their way out of a Ballas ambush. Michael and Franklin 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 making the news, 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. Dispatching his associate Wade to search for Michael, Trevor proceeds to settle 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. After the Triads decide to work with the O'Neil redneck family instead, Trevor kills all but three of the O'Neils and destroys their meth lab. Following all of this, he travels to Los Santos to confront Michael, none too happy with the guy for ditching him and Brad nine years ago.
Following Trevor's return to his life, 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 this work, Trevor leads Michael and Franklin in stealing a top-secret experimental device from Merryweather Security Consulting, a private security firm with permission to operate on US soil. The heist is a success, but Lester - who had been cut out of the planning for it - reveals the device to be a highly potent superweapon that would draw too much heat for him and the trio to deal with, and they are forced to return it before the theft is discovered.
Franklin begins assassinating corrupt businesspeople for Lester - who provides him a mansion in Vinewood Hills that he had bought as an investment - and he also reluctantly accompanies Lamar in buying a brick of cocaine from a dealer on Grove Street (Ballas territory in this iteration of GTA) in a deal arranged by Stretch. Trevor invites himself along to the deal, where he discovers the cocaine to be a mere brick of drywall shortly before the Ballas attack them in force, forcing them to shoot their way out. Franklin becomes convinced that Stretch set him and Lamar up, but Lamar is unconvinced. Meanwhile, Michael's relations with his family collapse after he attacks Amanda's yoga instructor and new paramour, and they all leave him. On the brighter side 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, Trevor and Lamar to steal a series of high-end cars for him.
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. While the two of them are hiding out at Trevor's place in Sandy Shores, they and Franklin deal with the last of the O'Neils, and Trevor attempts to hijack a Merryweather jet plane in midair, with the jet getting shot down by the air force. Trevor later leads Michael in derailing and then robbing a goods train being guarded by Merryweather, but Michael only steals an Aztec statue in order to placate Madrazo. He 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. The two of them draw guns on each other before being attacked by the Triads, who had mistaken Michael for Trevor's boyfriend after observing the two of them together, and now seek to use him as leverage to stop Trevor disrupting their operations in the region. Trevor flees and - enraged over the betrayal - sabotages Michael's car, leading to his capture by the Triads. He returns to Los Santos alone and assists Franklin and Lamar in transporting Devin's stolen cars out of the city, but the billionaire holds out on paying them when the job is completed. 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, with the evidence against Michael also being destroyed during the operation. Michael later meets up with Dave and Haines 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, the 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 cancel the production in order to claim the insurance money from it, with his attorney Molly Schultz confiscating the analogue copy of the film. Mistakenly believing the copy to be the only record of the film, Michael chases Schultz to and around the city airport, with the panicking Schultz getting sucked into a jet turbine in the resulting chaos. Michael and Solomon arrange a premiere for the film to to prevent any further attempts to cancel it, 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 up to 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 separate 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 - the latter of whom explicitly refused to help kill Michael - 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 a Los Santos foundry with a rumour about the stolen gold, anticipating that both Haines and Devin will want to retrieve it. After withstanding a massive assault from both the FIB and Merryweather, the protagonists proceed to wipe out all their enemies; Franklin kills Wei Cheng, Michael kills Stretch and Trevor kills Haines, before kidnapping Devin and locking him in the trunk of his own car, driving him away to Blaine County. Reuniting there, the protagonists take a moment to gloat at Devin before pushing the car off a cliff, killing the billionaire. They stop working together and carry on with their lives, but still remain friends.
