With some of the members on vacation, Iron Man, Thor and Hulk help out the Fantastic Four when Super-Skrull and his fellow Skrulls invade Super Hero City. Meanwhile, Thanos and Doctor Doom form an alliance in order to obtain a specific artefact from the Baxter Building. While the Fantastic Four and the other Super Hero Squad members are fighting the Skrulls, Falcon and H.E.R.B.I.E. defend the Baxter Building from Abomination, M.O.D.O.K., and Trapster.

M.O.D.O.K. and Loki conspire to overthrow Doctor Doom and take his place as leader of his allied villain group after M.O.D.O.K. eats one of the fractals. In order to stop M.O.D.O.K. and Loki, the Super Hero Squad and Storm must team up with Black Panther and an unlikely ally... Doctor Doom.