The Princess asks her daddy to destroy Danger Mouse, so he breaks her and 11 other villains from Arkwright Assylum to tire out DM before revealing himself to be his latest, greatest enemy.
Danger Mouse has been defeated by Augustus P. Crumhorn IV. Only Penfold refuses to give up hope that his beloved 'Chief' will still somehow return against all odds.
Big Head has been reprogrammed and renamed Big Head II. She captures all the world's criminals and imprisons them in a maximum security prison, then finds reasons to imprison all the Danger Agents as well.
While Professor Squawkencluck is away at the Chicken's of Rock Festival, a small plant in her laboratory grows into a Vicious Scrub and engulfs the entire world because Danger Mouse insists on taking care of it.
Various objects, including math tests and medals and even the moon, are being sucked into the Twystyverse by the evil Baron Silas Von Penfold who wants dominion over both worlds.
Penfold is attending the annual Side-Kickie Awards and wants Danger Mouse out of the way so he won't embarrass him as usual. But Stilleto is intend on making sure he wins the main award himself.
Elephant flu is infecting everybody in the world, transforming the entire population into elephants, except for Penfold who despises pachyderms because of a tragic incident.
An accident leaves Penfold and the Baron shipwrecked on one literal half of an island, separated from Danger Mouse and Stiletto. Forced to work together will Penfold's niceness and cooking be enough to get the Baron to change for the better?