Hank and Dean Venture, with their father Doctor Venture and faithful bodyguard Brock Samson, go on wild adventures facing megalomaniacs, zombies, and suspicious ninjas, all for the glory of adventure. Hank and Dean Venture are relatively identical twins, only born six minutes apart, who live for the thrill of adventure. Their dated vocabulary and high-pitched voices are intentionally annoying, especially to their father, Doctor Venture, a boy genius turned mediocre scientist who hates everything about his life. In the midst of this conflict is Brock Samson, a man of swift neck-breaking action. Preferring to resort to his brawn instead of his brain, Brock is simple but effective, and does a better job at taking care of the kids than Doctor Venture.
Dr. Venture's therapy group, a collection of former Boy Adventurers (who have become failed adults), quickly fall back into their old habits when a mystery is literally dropped into their session. Meanwhile, Sgt. Hatred tries to overcome his own past when he's stuck in a movie theater crammed with kids. History is doomed to keep repeating itself if Hatred and Dr. Venture can't break their cycles.
The Guild of Calamitous Intent comes under attack by an insane Phantom Limb, who now goes by the name "Revenge". Meanwhile, Hank and Sergeant Hatred must protect the compound from the Guild's agents.
Number 21 kidnaps the Venture brothers without The Monarch's knowledge or consent, resulting in Sgt. Hatred having to storm his former hometown of Malice to rescue his charges.
Rusty begins to indoctrinate Dean into his career as a super scientist, not knowing that a deformed and believed aborted Dean clone stalks the compound. The deformed clone's attempt to kill Dean leads to a mix up with Hank thinking that he's killed his brother, while local police prepare to raid the Compound after a UPS delivery man suspects illegal activities going on.
The Monarch attempts to get $10 million via kidnapping Hank and Dean and holding them for ransom. However, the plan is foiled when an old nemesis of his, a hero named Captain Sunshine, arrives and rescues Hank, making him his new sidekick, Wonder Boy.