[8] The game’s overall plot focuses around an Earth invasion by the G3 Cartel, led by Garmantuous (Hal Lublin) who intends to turn humans into drugs.

The player character, with their sister Lizzie (Laura Silverman), teams up with an alien named Kenny (Justin Roiland) to combat this threat.

The player, now a bounty hunter trained by Gene Zaroothian (David Herman), is tasked with defeating G3 leaders and rescuing captive Gatlians, a species with unique combat abilities.

They successfully defeat 9-Torg (Jennifer Hale), Douglas (Tom Kenny), and Krubis (Echo Kellum), recruiting two more Gatlians, Sweezy (Betsy Sodaro) and Gus (J.B. Smoove), and Knifey (Michael Cusack), a gleefully bloodthirsty sentient knife, along the way.

As the player gains notoriety, Blim City's Magistrate Clugg Nuggin offers them support, providing intelligence on G3 and equipment upgrades.

The player encounters more Gatlians, like Creature (Tim Robinson) and the powerful but catatonic Lezduit (Mike Stoklasa), while dealing with adversaries like the Skrendel Bros and Dr. Jon Giblets (Kevin McDonald).

The story concludes with Knifey returning to Earth, reaffirming his bond with Gene through his traditional stabbing gesture, and planning to settle unfinished business on Peroxis.

Development of High on Life began in 2019, a short time after the release of the studio's previous title, Trover Saves the Universe.

The initial concept, conceived by Justin Roiland, was to develop a first-person shooter that featured talking guns that would speak to the player and react to their actions.

B. Smoove, Tim Robinson, Betsy Sodaro, Michael Cusack, Hal Lublin, Laura Silverman, David Herman, Kevin McDonald, Mike Stoklasa, Tom Kenny, Echo Kellum, James Urbaniak, Maria Bamford, Joel Haver, Wayne Pygram, Andy Daly, Zach Hadel, Rich Fulcher, Thomas Middleditch, Jack Black, and Susan Sarandon.

In a positive review, IGN called it "an irreverent, absurd shooter that manages to shine with its outrageous humor, silly setting and story",[27] while Eurogamer criticized that the writing "too often settles into edgelord cynicism and the same tedious, punchdown humour as South Park.

"[28] The Guardian noted that "the line between entertaining and excruciating here is down to how you feel about listening to a game-length version of Rick and Morty's Interdimensional Cable ad-libs".