The actor appeared in three episodes of the last season as Eddie Nero, a movie star who had signed up to play Hank (David Duchovny) in a film.
Lowe has now confirmed on his Twitter page that he will be returning to the show.
"Had a blast with my pal David Duchovny on Californication yesterday," he said. "Wait till you see Eddie Nero's new look. Freaky as usual."
Other stars who are expected to appear in the next season of Californication include William & Kate's Camilla Luddington, Justified's Natalie Zea and Meagan Good.
The show's creator Tom Kapinos has previously suggested that the show could end after its fifht season.
Watch a clip of Rob Lowe talking about his role in the last season of Californication below: