Prior to the beginning of the series, the villainous Doctor Doom, in pursuit of universal domination, attempts to acquire the limitless reality-bending power of the "Infinity Sword." He is stopped by Iron Man, but as a consequence of their battle, the sword is shattered into numerous fractals that rain down on Super Hero City. Doctor Doom has forged alliances with just about every supervillain forming the Lethal Legion in order to hunt down the scattered fractals, each of which possess dangerous and different powers of their own. The second season revolves around the Super Hero Squad gaining a new team member (Nova, Captain Marvel, the Squadron Supreme, Hercules, Zeus, Annihilus and She-Hulk. Thanos is the one of the main villains.
Slowly going insane in prison, Doctor Doom leads an escape plan where he distracts the Super Hero Squad using a Fin Fang Foom balloon and must lead his former allies (and two new ones) to escape from the grasp of Captain America and Ms. Marvel.
A mishap between Thanos' new Time Gem and the Scarlet Witch's hex powers sends her back to World War II, where she must assist Captain America and the Invaders stop Red Skull from launching a rocket that will destroy Europe.
After the Super Hero Squad gets imprisoned by the Skrulls, Falcon's trump card, in the form of Scarlet Witch, is the only hope to stop the war between the Kree and the Skrull and to defeat Thanos and his Soul Gem.
When Captain Marvel goes missing during a peace conference between the Kree and the Skrull, Ms. Marvel forces the Super Hero Squad to come together again to get to the bottom of this, unaware that Thanos is behind this. Meanwhile, Doctor Doom plans a prison break with Wrecker and Thunderball.
Galactus arrives in Super Hero City to devour the Earth! The fate of the planet hangs in the balance, but all of the city's heroes are powerless before Galactus.