Following the events of Chicago, San Francisco becomes the next city to install the CTOS (central Operating System), which connects everyone with everything. Marcus Holloway, an intelligent hacker from Oakland, California, is punished for a crime he did not commit by the upgraded CTOS 2.0 system, which categorizes him as the suspect. Realizing the system covertly brings harm to the innocent citizens of San Francisco, he decides to work with the hacking group DedSec to take down the city's CTOS 2.0, and Blume, the company behind it.

Marcus joins DedSec and works with fellow hackers Sitara, Wrench, Horatio and Josh, and they begin using their skills to expose corrupt organizations and corporations that are secretly using stolen personal CTOS data for their own personal gain. The game begins with Marcus's DedSec initiation test: deleting his own CTOS profile from the database. Being successful, he is accepted into DedSec. He is soon alerted about a fake church called New Dawn that serves as a criminal organization. Eventually, Marcus stumbles upon the existence of Bellwether, a data manipulation program being fed CTOS data by Dušan Nemec, Blume's CTO, to manipulate world finance and politics. DedSec later manages to recruit the assistance of old-time hacker Raymond "T-Bone" Kenney, who is determined to battle Blume.

With his assistance, DedSec manage to expose the corruption of the FBI and numerous Silicon Valley corporations, such as Nudle, Tidis, and Galilei, and take down the ringleaders of the Tezcas, a violent street gang who kidnapped DedSec member Horatio Carlin and killed him after he refused to cooperate with them. Learning that Blume is planning to install a satellite network designed to bypass undersea data cables, which would effectively give Blume a monopoly on the entire world's electronic data and stock exchanges, they infiltrate the launch area of one of the satellites to install a backdoor. In order to bring down Blume and Dušan for good, Marcus breaks into Blume's San Francisco headquarters and hacks their servers, exposing the existence of Bellwether and Dušan's corruption. Dušan is arrested for fraud and Blume is put under investigation, though DedSec resolve to continue their fight against Blume.

In an extended ending scene added in a post-release patch, two unidentified individuals note that more DedSec cells and hacktivist groups have been emerging worldwide in response to the San Francisco Blume scandal, and that it is time to put their own plans into motion, possibly signaling a third Watch Dogs game.