The comedian will feature in the Showtime series as rock star Atticus Fetch, who works with Hank Moody (David Duchovny) on a rock musical while "doing a lot of cocaine".
Speaking to Digital Spy at the We Will Rock You 10th anniversary performance in London, Minchin said that he was grateful to make such a "significant" return to acting.
"I was an actor back in the old days before I found comedy," he revealed. "And I've been looking for an opportunity to get back into acting but I didn't think it would be quite this significant, so I'm very excited."
Minchin also admitted that he "didn't know anything about" Californication before landing the role, but has since become a fan.
24 actress Sarah Wynter will portray the wife of Minchin's character.
In addition to his Californication role, the Australian comedian will play Judas in Lord Andrew Lloyd Webber's revival of Jesus Christ Superstar.
Spice Girl Melanie C (Mary Magdalene) and Radio 1 DJ Chris Moyles (King Herod) are also appearing in the production, while the role of Jesus will go to the winner of upcoming ITV contest Superstar.