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.

With Kuo and Nix's help, Cole undermines Bertrand's influence over New Marais, eventually discovering that Bertrand, who is also a Conduit, has been transforming large numbers of kidnapped civilians into mutants so that he can terrorize the people into supporting him. Nix explains that when she was young, Bertrand, then a member of the First Sons, used a Ray Sphere built by Wolfe to gain powers, killing hundreds of innocent people, including her mother. After realizing that his "powers" were only capable of turning him into a deformed monster, Bertrand vowed to cleanse the world of Conduits by unleashing hordes of them upon the world in the hope that humans would ultimately rebel and exterminate them. With the Conduits and the resistance movement joining forces, Bertrand is killed in his mutated form, ending his tyrannical rule.

With the Beast just miles away from New Marais, Cole reunites with John White (Phil LaMarr), who he thought had died in the process of destroying the first Ray Sphere. John admits that he has become the Beast and gives Cole a vision of humanity perishing from a plague born of the radiation from the "Empire Incident". As Conduits are immune, White claims that the only way Cole can save the world is to turn his back on humanity. After locating the last core, Cole prepares to activate the RFI. However, he realizes that while doing so will cure the plague, it will also kill every Conduit on Earth. Kuo abandons humanity out of fear and sides with White, while Nix sides with humanity since she will no longer be special in a world of conduits.