The two main characters of the show are Killface, who is a naked, bone-white, red-eyed, earless, talon-toed, spur-heeled, 7-foot-tall (2.1 m), 440 lb (200 kg), hairless, muscular humanoid supervillain focused on destroying Earth with his invention, the Annihilatrix;[4] and billionaire tycoon Xander Crews, who fights crime under the superhero alias Awesome X.

Other major characters include Killface's son Simon – voiced by Christian Danley – an overweight, blond-haired, pale-skinned, sexually confused, teenaged Hannah Montana fan, who wears sweater vests and exhibits adolescent rebellion by muttering and breaking cereal bowls;[6] reporter Grace Ryan, former girlfriend of Xander Crews turned into Antagone, a toxic, radioactive ant-powered villainess; Sinn – voiced by Kelly Jenrette – later known as Hooper, originally Killface's sidekick and later his enemy;[7] and the Xtacles, Awesome X's team of easily distracted and remarkably inept, rocket-booted troops.

Despite its lack of a specific name, maps of "Town" are featured throughout the series, which closely resemble interstate roadmaps of the city of Atlanta, Georgia, where 70/30 Studios, producers of Frisky Dingo, were based.

Additional evidence for "Town" being Atlanta is the presence of buildings suspiciously resembling the Cotton Mill Lofts (a location that at one time housed production operations for 70/30) burning in the second episode, "Meet Awesome-X".

The first season of Frisky Dingo follows the adversarial relationship between the villainous Killface, who aspires to strike fear into humankind before he drives the Earth into the Sun with his Annihilatrix, and Awesome X, the secret superhero identity of multibillionaire Xander Crews, who dreads retiring after having defeated the last known supervillain.

At the beginning of the second season, Killface is taking credit for "curing" global warming due to the Annihilatrix having moved the Earth a total of three feet further from the Sun before it malfunctioned, and has decided to run for President of the United States.