Trevor Munson originally conceived the character in 2004 as 'Mick Angel' and spent two and a half years writing a novel about him before adapting it into a feature film script, for which Bruce Willis was considered for the lead role.

The project was originally titled 'Twilight' when Ron Koslow and Trevor Munson wrote the pilot, and it was only renamed 'Moonlight' when CBS picked it up in May 2007, prior to the network upfronts.

Showrunner David Greenwalt, co-creator of Angel, was brought on in May 2007 to restructure the original concept, but health reasons forced him to leave the series, and Chip Johannessen took over as showrunner in August 2007.

When the pilot was reworked, every original lead actor except Alex O'Loughlin (Mick) was recast in June 2007: Shannon Lucio, Rade Šerbedžija and Amber Valletta were replaced by Sophia Myles, Jason Dohring and Shannyn Sossamon, requiring a full-length pilot to be reshot with the new cast.

Producer Joel Silver approached Jason Dohring 'out of the blue' offering him the role of Josef by making the character younger, though Dohring still had to go through the standard audition process.

The cast was deliberately made younger to make the show 'hipper', particularly for the Josef role, since original actor Rade Šerbedžija was twice Jason Dohring's age and producers feared this would make Josef seem like a father figure to Mick rather than a friend.

Despite mostly negative reviews, the pilot episode 'No Such Thing as Vampires' finished first among total viewers and adults 18-49 for its night, drawing 8.54 million American viewers.

Fans organized charity blood drives with the American Red Cross across 33 states in connection with the show, and lead actor Alex O'Loughlin became a national spokesman for the charity.

Production was halted by the 2007-2008 Writers Guild of America strike, resulting in only twelve of the originally ordered thirteen episodes being produced before four additional episodes aired once the strike ended; the show was cancelled by CBS on May 13, 2008, and later attempts to sell it to other networks, including Media Rights Capital and Syfy, ultimately failed.