In the main game, the player controls Cadence, the daughter of a famed treasure hunter who has gone missing. In searching for him, she falls into a crypt controlled by the NecroDancer, who steals Cadence's heart and forces her to challenge his minions to retrieve it. She is forced to fight through the crypt's dungeon with her actions tied to the beat of the music and her heart, so as to stay alive and defeat the NecroDancer.

Near the heart of the crypt, Cadence finds one of the NecroDancer's minions named "Dead Ringer". She defeats him, revealing that it was her missing father and frees him from the NecroDancer's control, allowing him to help her defeat the NecroDancer. They take the NecroDancer's magical golden Lute and use it to kill him, and then use its power to resurrect Cadence's dead mother, Melody. However, they discover that the lute is cursed; Melody must keep playing it forever to sustain her life, but the lute will gradually consume her humanity just as it did to the NecroDancer. Melody enters the crypt in search of answers and a way to break the curse of the lute.

When Melody reaches the end of the crypt, she uses the Golden Lute to resurrect the NecroDancer and find answers, but he attacks and Melody defeats him. The NecroDancer tries to flee but is cast into a crevice by Aria (Melody's mother) who was lying in a coffin with a dagger in her chest and is brought back to life by the Lute. Aria reveals that she knows how to break the curse of the lute, but was betrayed by the NecroDancer and left for dead. Intending to finish what she started, she begins her ascent out of the crypt in search of a shrine that will destroy the lute once and for all.

When Aria reaches the shrine, she is attacked by the lute itself, which mutates into a large monster in an attempt to save itself from destruction. After defeating the lute's monster form, Aria sacrifices her life to destroy the cursed instrument, returning Melody to full life and allowing her to return to her family, who later bury Aria together.