Creators Brendon Small and Tommy Blacha came up with the idea while attending metal shows together after Small's previous show Home Movies ended in 2004, imagining a band vastly more popular than The Beatles.

The show was originally titled Deathclock, but the name couldn't be used due to an existing trademark, so it was changed to Dethklok, then briefly Dethklok Metalocalypse, before being shortened to just Metalocalypse.

Adult Swim greenlit the series in 2005 with a 20-episode contract after Small and Blacha pitched it, having also had friend Jon Schnepp design the characters.

To determine the show's budget, Small researched what he considered the cheapest Adult Swim show to produce, Tom Goes to the Mayor, learning from Tim and Eric that it cost $110,000 per episode; animation studio Titmouse then agreed to produce Metalocalypse for $109,099 per episode averaged over a season.

The Metalocalypse premiere was the #1 rated show in its time slot among males aged 18–34 and earned Adult Swim's best premiere delivery and ratings of 2006.

Actor Mark Hamill claimed in 2013 that a fifth season was in production, but Brendon Small publicly denied this, saying it had not yet reached production.

Dr. Rockso was designed as an amalgam of hard-rock frontmen like Vince Neil, Axl Rose, and Bret Michaels, though animators ultimately made him resemble David Lee Roth.

The band Snakes N' Barrels, Pickles' first band, is a reference to Guns N' Roses.

After the show's cancellation, Small launched a fan campaign called 'Metalocalypse Now' in 2015 to convince Hulu and Adult Swim to co-fund a series finale, and financial backers stepped forward, but Adult Swim ultimately declined to pick it up.

The Doomstar Requiem soundtrack album featured, for the first time on a Dethklok album, live Dethklok touring guitarist Mike Keneally alongside a 50-piece orchestra.