Na de vernietiging van Empire City pakt Cole MacGrath zijn spullen en gaat hij op reis naar het zuiden, om precies te zijn naar New Marais. Daar ontdekt hij dat zijn krachten nog steeds aan het groeien zijn, je begrijpt dan ook wel dat dit nooit lang goed kan gaan. Waar Cole oa mee te maken krijgt is The Beast, en hoe dat zit kan je in de onderstaande trailer zien.

What's the Beast, you ask? Like a meteor from outer space it's a force of destruction too powerful for humanity to contain. At the end of inFamous, Cole MacGrath was given a vision that the Beast would arrive into the world and that he alone could stop it. The safety of our species was put on his shoulders. No pressure right? As you might imagine Cole would do anything in his power to get ready for the fight. He's desperate to win, to save the lives of his friends and neighbors.

But at the start of inFamous 2 he fails. The Beast arrives and Cole isn't strong enough. He's forced to run south to New Marais and prepare for a second, final encounter while his home, Empire City, is swallowed in flames.