The year is 2049, and Tokyo is in the midst of dangerous street riots. Dr. Kosugi, a scientist working for the A.R.M.A. corporation, has created three "mutanoids" - powerful bio-engineered fighters who regard him as their father. When they find out that Dr. Kosugi is missing, they venture into the dangerous areas of the city to bring him back and punish the culprits.

Crimson Tears is an action game with role-playing elements. Controlling either of the three protagonists (Amber, Kadie, or Tokio), each with their own strengths and weaknesses, the player explores randomly generated, enemy-infested stages, disposing of the foes in combo-based hack-and-slash combat. Experience points are gained from battle victories, allowing the characters to level up and become stronger.

Weapon components can be collected from fallen enemies and combined to make new weapons. Like the characters themselves, weapons level up, increasing in attack power and reducing the necessity to repair them. The protagonists have access to ranged attacks, blocks, and powerful area attacks. The player should also keep an eye on their temperature meter, preventing them from overheating.