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.
As Thanos gets all the Infinity Stones, the Squaddies face betrayal at the hands of one of their own! In this mind-shattering climax to the Infinity Gauntlet Saga, the very fate of the universe hangs in the balance.
Doctor Doom returns to Latveria in hopes to regroup, but discovers that his mother Coco is free from captivity, has brainwashed her captor Chthon, and has turned his castle into a day-spa trap that has ensnared the Super Hero Squad!
An army of Wolverine clones invade Super Hero City, forcing the real Wolverine and Reptil to get to the source with help of Firestar. Outside of the other Super Hero Squad members rounding up the Wolverine clones, Reptil is unaware that his science fair partner and Firestar are one person.
Thanos destroys the Nova Corp and takes Nova captive in order to get his hands on the Power Gem, leading to Iron Man to recruit Hercules and She-Hulk to rescue him. Meanwhile, H.E.R.B.I.E. falls for Nova's messenger droid named Holoball.
Enchantress places a love spell on Odin in an attempt to become queen of Asgard, but a forgotten rule forces him from the throne and makes his son Thor king instead, which both she and Loki try to take advantage of. Meanwhile, Magneto and Quicksilver discover Wanda joining with the Super Hero Squad and hitch a ride to try and take her back from them.