Second Son takes place in 2016, seven years after Infamous 2's Conduit protagonist Cole MacGrath sacrifices himself to cure humanity of a plague and destroy The Beast. Cole uses the powerful Ray Field Inhibitor weapon, which kills him and most of the other Conduits. The U.S. government establishes the D.U.P. to hunt down and capture the world's remaining Conduits, dubbing Conduits with the pejorative "Bioterrorists ". The protagonist is Delsin Rowe (Troy Baker), a 24 year old graffiti artist and the local delinquent of the Akomish reservation. Delsin has the unique Conduit ability of Power Mimicry, allowing him to copy the powers of any Conduit he comes into contact with. His brother, Reggie (Travis Willingham), is the local sheriff, and often arrests Delsin for his acts of vandalism. Both are Akomish Native Americans, whose territory lies at the shore of Salmon Bay, Washington. The antagonist is Brooke Augustine (Christine Dunford), the director of the D.U.P. and a Conduit with power over Concrete. Her actions in the Akomish reservation drive Delsin to travel to Seattle, now under lockdown by D.U.P. forces. Delsin and Reggie encounter three other Conduits: Henry "Hank" Daughtry (David Stanbra), a convict with control over Smoke; Abigail "Fetch" Walker (Laura Bailey), an ex-junkie who uses her Neon powers to hunt down illegal drug dealers in Seattle; and Eugene Sims (Alex Walsh), a reclusive video game addict who uses his Video (digital materialization) powers to save suspected Conduits from the D.U.P.

after Reggie catches Delsin vandalizing a billboard, their subsequent argument is interrupted when a military truck carrying three Conduit prisoners crashes on the Akomish reservation. Two of the Conduits escape, but Delsin manages to pull the third one, Hank, out of the wreckage, inadvertently absorbing his smoke powers in the process. Shocked and frightened, Delsin pursues Hank in an effort to figure out what has happened and how to control his powers. However, they are both cornered by Brooke Augustine. She encases Hank in concrete and questions Delsin, suspecting him of hiding something. Delsin can choose to either tell Augustine the truth about his powers or say nothing. Regardless of Delsin's choice, Augustine knocks him out before moving on to the other tribe members.

Delsin awakens a week later and discovers that Augustine has tortured the rest of the tribe in an unsuccessful bid to gain information. However, she has left them to gradually die from concrete shards buried into their bodies, including their leader Betty (Karen Austin). Reggie, who was spared from the torture, learns that the only way to remove the shards is to use Augustine's power on them. Delsin realizes that he can absorb Conduit powers and resolves to go to Seattle to take Augustine's powers and save the tribe. Reggie reluctantly accompanies Delsin to keep an eye on him. They reach Seattle and find that it has been put under strict martial law by the D.U.P. in order to find the other escaped Conduits. With Reggie's help, Delsin battles D.U.P. forces and tracks down core fragments to develop his powers. He eventually encounters the other two escaped Conduits, Fetch and Eugene, and absorbs their powers. After both confrontations, Delsin defends the Conduits from Reggie, who initially views them as "freaks", and can choose to either redeem or corrupt them.