Stink Moody, friends Webster and Sophie, and Mrs. Birdwistle visit tourist attractions in Virginia as they try to give away 101 guinea pigs rescued from a laboratory, although Stink is very reluctant to give away his favorite, Astro.

While his human Elliot adjusts to his new home and stepfamily, Gizmo, an evil genius guinea pig, searches for a new evil lair where he can plot to take over the world, but Gizmo is constantly thwarted by Elliot's little stepsister Jasmine (who likes to play dress-up), Abuela (who may or may not like to eat cavies), and Wedgie (a Corgi superhero and Gizmo's nemesis).