In mid-1998, Zombie made his solo debut with the album Hellbilly Deluxe; when it sold more copies in its first week of release than any White Zombie record before it, he disbanded the group to forge ahead as a full-time solo act, issuing American Made Music to Strip By in the fall of 1999. Starting his own label, Zombie-a-Go-Go Records, he gave bands like the Ghastly Ones a home while creating demented mix CDs like Halloween Hootenanny. He delivered remixes to a number of soundtracks while recording a new song for the Mission Impossible: 2 soundtrack, and he rounded out his first major solo run with a Rob Zombie toy produced by Todd McFarlane.

He began to work on a feature film in April of 2000, funded by Universal Studios after he designed a horror display for their amusement parks. The film, entitled House of 1000 Corpses, was produced and edited, but the studio backed out due to its own corporate standards. Zombie wrangled the rights to the film from the studio while taking out his frustrations on his next solo record, Sinister Urge. Again working with collaborator Scott Humphrey (who had produced his first record), he drafted in a metal superstar cast including Ozzy Osbourne, Slayer guitarist Kerry King, Mötley Crüe/Methods of Mayhem drummer Tommy Lee, and Limp Bizkit's DJ Lethal. The record was another success, leading to a huge Christmas tour with Osbourne at the end of 2001 and another solo tour in the spring of 2002.

Zombie sold House of 1000 Corpses to MGM for a Halloween release, although offers from several smaller studios had to be refused because of the financial loss he would have taken. The film was a cult hit, prompting Zombie to begin work on his next piece of celluloid, 2005's Devil's Rejects. He returned to the recording studio in 2006 for Educated Horses, a typically sinister collection of B-movie swagger that hit the Top Ten of the Billboard album charts. After a stint as director and co-writer of the 2007 remake of Halloween, Zombie Live, his first live album, was released in October 2007, the same month that he began an arena tour with Ozzy Osbourne. The release of his next studio album was pushed back due to Zombie's involvement with Halloween II, and in 2010 Zombie released Hellbilly Deluxe 2, his first solo album written with the help of his band (which featured John 5 and Piggy D.). A remix album, Mondo Sex Head, arrived in 2012. A year later, Zombie returned with the all-new studio album Venomous Rat Regeneration Vendor.