In inFAMOUS 2, people with superhuman abilities, called Conduits, exist. Since the creation of the first Conduit, Cole MacGrath, the emergence of others has unsettled human society. At the same time, Cole has learned from his future self, Kessler, that a powerful Conduit known as the "Beast" will rise to destroy the world and that only he has the power to defeat him.

Story Following the events of InFAMOUS, Cole (Eric Ladin) and his friend Zeke (Caleb Moody) meet with NSA agent Lucy Kuo (Dawn Olivieri), who informs them that Dr. Sebastian Wolfe (Michael Ensign), the man responsible for creating the Ray Sphere that gave Cole his powers, has developed an even stronger version that would give him enough strength to stop the Beast. Before they can depart for Wolfe's lab in New Marais, the Beast attacks Empire City. Cole tries to fight him off, but even his most powerful attack proves useless. The group is subsequently forced to flee as Empire City is completely and utterly destroyed.

Arriving in New Marais, Cole and his allies learn that energy magnate Joseph Bertrand III (Graham McTavish), an anti-Conduit demagogue, has seized control of the city. Aware of Wolfe's intentions, Bertrand has his private army, the Militia, destroy the doctor's lab. Rescuing Wolfe, Cole learns that he has developed the Ray Field Inhibitor, a device capable of stripping Conduits of their powers. Before he can help Cole locate the energy cores needed to power the RFI, he is killed by the Militia, who also take Kuo captive. While working to free her, Cole and Zeke meet Roscoe Laroche, a Vietnam veteran who leads a resistance movement opposed to Bertrand, and Nix (Nika Futterman), a Conduit with the ability to manipulate and ignite a black, napalm-like substance, who has been waging war on the Militia. Using intelligence gathered by Zeke, Cole and Nix locate a secret lab where Kuo, revealed to be a Conduit, has been forced to transfer her ice-generating powers to an army of human mercenaries controlled by Bertrand. The two free her, but also end up releasing the mentally unstable mercenaries into the city.