It has been nearly 1 year since Skylar, Kaz and Oliver became friends and Kaz and Oliver throw a party to celebrate their friendship. However, the boys learn not only is Skylar is in danger of losing her powers forever but she will also die. The boys help Skylar when in order for Skylar to reclaim her powers, she has to fight her nemesis The Annihilator. At the same time, Wallace and Clyde trick Alan into getting them the other half of the Dyad of Nebulos which they use to become Catastrophe again as he plans to get revenge on Horace. During the fight against the Annihilator, Megahertz and Experion show up to fight after escaping from Mighty Max Prison. The boys, Skylar and Alan must work together to stop a deadly villain infestation, prevent the Annihilator from keeping Skylar's powers, and keep Mighty Med also Horace from being destroyed forever. Catastrophe captures Horace but Alan steals the dyad and destroys it. Experion, Megahertz, Wallace and Clyde are later arrested by Mighty Med Agents and are placed in the Mighty Max Prison. In a twist ending, it is revealed that Annihilator had tampered with Skylar Storm's powers during their battle to make her serve the Annihilator who plans to take over Mighty Med.