White previously directed Dern in the film "Year of the Dog," which he also wrote.
The Hollywood Reporter said production on "Enlightened" is expected to begin this summer in Los Angeles. White and Dern reportedly came up with the story for the series and will executive produce it.
Luke Wilson, Dern's mother Diane Ladd and Sarah Burns appeared with Dern in the pilot for the show.
"I'm stoked to finally party with HBO," the entertainment industry trade newspaper quoted White as saying. "I feel lucky to have been given this opportunity to make something original, heartfelt and weird."
"Creating a series with the ever-brave HBO and Mike White has been an incredibly exciting journey for me," Dern said. "I'm madly in love with my character Amy."
In the show, Dern will play a self-destructive woman who has an epiphany in a treatment center, then sets out to live an enlightened life.