Metalocalypse follows the exploits of the part-American/part-Scandinavian death metal band Dethklok. Dethklok follows true-to-life metal styling, one example being their death metal-oriented song, "Murmaider," about "mermaid murder." They enjoy a popularity level unheard of in reality, rising to become "the twelfth largest economy on Earth" (larger than Belgium). They are so popular that impressionable fans will often do anything their songs tell them, even if it means death. If Dethklok endorses a product or service, it quickly drives every competitor out of business.

The band's unnatural popularity has attracted the attention of an Illuminati-style group, known as the Tribunal. Each episode sees this group attempt to covertly thwart the band by calling in various "specialists", such as "military pharmaceutical psychotropic drug manufacturers", "celebrity depression specialists" or various psychopaths that attempt to infiltrate the group. It is alluded to on the show that several Washington think tanks specifically related to the band exist.

The band's concerts are notoriously violent, often resulting in harm to a good portion of the crowd. Even their attempts at charity result in numerous deaths, such as the laser light show that butchered the London Philharmonic orchestra during a benefit concert, and an entire island being maimed by "wayward kitties". The premiere episode gives an example of this: a giant metal box that serves as the band's stage is airlifted and parachuted on location, but misses the landing area and crushes much of the audience, both by virtue of its landing and by its subsequent opening. Several searing hot coffee and cream pitchers are also poured on the crowd, melting their skin off (to fit with the death metal styled coffee jingle being played by the band). Despite the obvious danger people love Dethklok's concerts so much that they will sign "pain waivers"[3] at the entrance, signing their lives away and releasing the band from legal liability in the very likely case they are killed or dismembered.

The members of Dethklok are portrayed as generally sociopathic and inept in all things non-musical except for negotiating their own contracts. Despite the band's immense success and talent, all of the members have self-esteem issues which surface to varying degrees during the show. Their monumental wealth allows them to get away with just about anything, including manslaughter. The band members share an obsession with "brutality" and "metal-ness," often choosing whether or not to do something based on how "metal" they believe it to be. Two members of the group suffer from extreme alcoholism, so drunkenness is often a plot device. The Band also show a great love of money. The Episode "Fatklok" shows the band perform a variety of charitable acts in order to prevent them having to pay tax. Similarly in the episode "Murdering Outside the Box" the band is shown to care very little about how they spend the money just as long as they have it, with Nathan Explosion emptying a bag of watches onto a table and smashing them but screaming when he discovers someone is embezzling the band.

The band members reside together in a vast mansion called Mordhaus (German for "Murder House") in an unspecified mountainous region known as Mordland.