Enlightened was created by Mike White, who wrote every episode, together with Laura Dern, and was pitched to HBO in August 2009 with Dern already attached as star.

The creators originally envisioned Enlightened as a trilogy across three seasons, each with a different moral compass and theme, telling a story of 'falling apart and then getting it back together.'

Diane Ladd, who plays Amy's mother Helen, is Laura Dern's real-life mother.

Mos Def was originally cast as Amy's boss Dougie, but withdrew due to a dispute over his deal, and the role was recast with Timm Sharp.

Creator Mike White also co-starred in the series himself, playing Amy's shy coworker Tyler, and directed the pilot episode as well as writing it.

Despite low ratings that led to its cancellation, Enlightened's second season received widespread critical acclaim, scoring 95 out of 100 on Metacritic and a 96% approval rating on Rotten Tomatoes.

Several prominent critics, including from The A.V. Club, Salon, and The Huffington Post, publicly campaigned for HBO to renew the show after news broke of its uncertain fate, but HBO canceled it in March 2013.

Laura Dern won the Golden Globe for Best Actress in a Television Series Musical or Comedy for her role as Amy Jellicoe, and was later nominated for a Primetime Emmy for Outstanding Lead Actress in a Comedy Series.

Mike White revealed that had the show continued into a third season, the story would have centered on a major lawsuit between Amy and Abaddonn Industries, exploring a satirical take on the legal world similar to how the show satirized corporate culture.

In July 2021, Mike White told The New Yorker that HBO had expressed interest in a one-off special or movie to wrap up the series, though he felt doing so at that time would feel like pandering rather than a bold creative choice.