He was voiced by Liam O'Brien.
In the special, he teamed up with Venom, Whiplash,and MODOK to fight off Hulk, Thor, Spider-Man, and Iron Man. After the four heroes defeated Whiplash and Venom, Red Skull appeared alongside MODOK to reveal his latest weapon: an antimatter device controlled by MODOK. The heroes overcome his weapon and were about to apprehend Red Skull and his comrades, but a ray from the sky zaps the heroes and drain them of their powers. This gave Red Skull and the other villains the chance to escape.
At the villains' evil lair, Red Skull was observing the video of the ray draining the heroes of their powers. Venom and Whiplash told him that they could have destroyed the heroes once and for all if they didn't retreat. Despite this, Red Skull tells them that it doesn't change the fact how the heroes have lost their powers. Red Skull then calls for MODOK, who explains to him that the ray came from a machine created by Heinz Doofenshmirtz after he read Doofenshmirtz's online blog about it in the L.O.V.E.M.U.F.F.I.N. webpage. Red Skull comments about the name Doofenshmirtz, saying that it reminds him of his cousin who married a Drusselsteinian and said she was dead to him. He then asks MODOK where to find Doofenshmirtz. MODOK informs Red Skull that Doofenshmirtz lives in Danville. Red Skull tells his comrades that they're going on a trip to Danville.
The villains arrive at Doofenshmirtz's building, where Red Skull introduced himself and his villains to Doofenshmirtz, who comments about his face, telling him to use sunblock as he tells him he is burned to the bone. Doofenshmirtz explained that his machine (known as the Power-Draininator) is what deprived the heroes' powers in the first place, and that he was intending to use it to take over the Tri-State Area. Red Skull demands for Doofenshmirtz to show the -inator, but Doofenshmirtz confessed that his nemesis Perry the Platypus has destroyed the -inator after the ray was fired, much to Red Skull's anger. However, Red Skull is delighted to hear that Doofenshmirtz is intending to build a second (but powerful) -inator based on the same idea, so he and his villains agree to help him out in getting the materials he need.
After getting the materials that they need for the -inator, Doofenshmirtz was able to fix up his new -inator to full power. Delighted by this, Red Skull betrays Doofenshmirtz by trapping him in a cage, revealing his true plan to use the -inator to deprive all superheroes of their powers and destroy the entire Tri-State Area. Red Skull also spots a disguised Perry spying on them and has Venom to trap Perry in a cage as well. Stealing the -inator, Red Skull and his villains head over to City Hall to announce their plot, even having MODOK to make a few modifications that can make the machine drain living energy and matter. Despite their lack of powers, the heroes go off to confront the villains aided by Perry, who manages to free himself and Doofenshmirtz from their cages. Eventually, Candace and Isabella soon discovered that the heroes' powers are held in a data collection tank in a space station built by Phineas and Ferb. They land the station in Danville and restore the heroes' powers, much to the dismay of Red Skull and his villains. After a brief fight against the heroes, Red Skull and his villains are arrested and taken into S.H.I.E.L.D. custody.