Lollipop Chainsaw is a hack and slash action game with gameplay resembling No More Heroes series, featuring a zombie-slaying cheerleader named Juliet Starling as the main protagonist. The locale for the events is San Romero High School. Everything began in Juliet's classroom, whereas a schoolmate of hers started to turn students into zombies in order to undo the barrier separating our world and Rotten World, a dimension where demonic and undead beings dwell. Juliet now has to rid the school of the undead outbreak.

Three categories of attacks may be performed: Light attacks (acrobatic kicks and punches by using her pom-poms), Heavy attacks (furious chainsaw slashes), and Super attacks (used for killing zombies and saving classmates will fill up Juliet's star meter). Juliet also carries the disembodied head of her boyfriend, Nick, who was bitten by a zombie and hangs him with her skirt, can be used as a projectile device. Juliet can place Nick's head and attached on a zombie's decapitated head and allows the player to control Nick possessing the zombie's body while assisting Juliet. When the player completes certain challenges in the game, Juliet's chainsaw and skills will be upgraded, gaining new abilities as you progress further into the game. By killing many zombies, it can earn you two types of medals (which are used from an in-game shop called Chop2Shop.zom). The gold medals are used for upgrading the character's stats and buy new signature moves, while rare platinum coins can be rewarded for killing special zombies or Sparkle Hunting.

Massacred zombies jet bursts of light instead of blood. Depending on some conditions, one or another of two different endings, a good and a bad one, will be displayed.