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.
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.
Thanos uses the Mind Gem to control Hulk who goes on a sleepwalking rampage. The Super Hero Squad must enter the dream realm to fight back, even if they have to get help from Nightmare.
With Galactus attempting to eat the Skrull Throneworld and the Silver Surfer nowhere to be found, the Squad must hold off the devourer while finding their ally. Silver Surfer (who is slowly being corrupted by the Infinity Sword) turns out to have delayed Ronan the Accuser from coming to the Skrull Throneworld's aid.
After stealing the Space Gem from Thanos, Nebula seizes the teliporter of the Helicarrier to get away, but sucks herself, as well as H.E.R.B.I.E. and Wolverine, into the Negative Zone where Annihilus attacks them thinking they're after his Cosmic Control Rod.