The game is set in Tokyo in the year 2049 and revolves around three characters whose home has been destroyed. As seen on the game's front cover, this trio seems human; however, they are actually bio-engineered weapons developed by a company named A.R.M.A. called "mutanoids".
- Amber - Created in the form of a nineteen year old woman, Amber is a deadly melee fighter. She's fairly balanced in terms of health, defense and attack power. She's quick with her weapons and agile defense, and she can wield a large variety of bladed weapons. In combat, Amber's most notable ability is her use of twin bladed weapons to decimate her enemies in a flurry of strikes. When she is equipped with one sword, knife or blade, the player can select a second weapon of the same type from her inventory to have her dual-wield both weapons. For instance, she can wield two Japanese swords simultaneously, but not one blade and one knife. While this ability devastates almost any foe, it also causes Amber's meltdown gauge to rise rapidly. To use Amber throughout a long dungeon, the player must use a lot of Cooling items, probably more than can be carried into the zone, or else she should wield only one weapon for part of the trip.
- Kadie - Kadie is the youngest of the group, both in her crafted appearance and in terms of her time in existence. She appears to be sixteen years old, but in reality she's even younger. This doesn't show through in her fighting, though. She's a skilled combatant, despite her naiveté. Kadie's strength lies in her high attack power, and in her ability to wield the heavier weapons. She's the only character that can use the fast Combat Claws and the dangerous Buster Sword. She has lower defense and health than the other two, which is her weak point, but she's quick enough to avoid a lot of attacks and can really dish out some damage of her own. She has no dual-wielding ability, but because of this, her meltdown gauge is easier to keep under control.
- Tokio - Although Tokio looks like the muscle of the group, his inherent abilities are geared more toward defense. He has the highest defense and health in the trio, letting him take more abuse before finally succumbing in battle. The tradeoffs are that he can't deal as much damage in melee combat, and his attacks and movements tend to be slower than those of the girls. As well as having the most stamina, Tokio also has an affinity for ranged weapons. To start with, he has a weapon called the Psy-Gun, which allows him to convert his mental energy into a ranged attack using no ammunition. This comes at the expense of a slight rise in the meltdown gauge. He is also the only character capable of dual-wielding ranged weapons, with the same restriction that applys to Amber. Using this ability, Tokio can target more than one enemy at a time for ranged attacks, often letting him emit a hail of bullets that can keep a crowd of foes at bay.
- Lana - This telepath serves as the link between the trio and their past with A.R.M.A. She has a near-constant connection to the main characters, and gives them information to guide their steps throughout their quest.
- Dr. Kosugi - One of A.R.M.A.'s scientists, Dr. Kosugi created Amber, Kadie and Tokio, and the trio see him almost as a father. Since the recent riots in the streets, the doctor has gone missing and it's up to the main characters to locate him.
- Abel - Abel is a fellow humanoid bioweapon, also created by Dr. Kosugi. He too has gone missing, but this dangerous individual is more than capable of taking care of himself, even in the monster-infested dungeons. It's hard to tell at any point just what he's thinking, or whose side he's on.
- Eden - While the trio have Lana, Abel has Eden to act as his telepath and confidant. A mysterious humanoid unknown by the main characters, Eden's creation is somehow different from their own.
- Vixor - The final boss of Crimson Tears, Vixor is also the head of A.R.M.A., and he's a manipulator on a grand scale. He's the puppeteer lying behind many of the events that transpire throughout the game. He's always calm and in charge despite the chaos outside his high vantage point in the A.R.M.A. corporation. Although he likes to sit on the sidelines and watch things fall into place, he will step in if he feels things require a more personal touch.
The player may send one of three different mutanoids, each with different statistics, into a dungeon in order to ultimately reach the boss. Each dungeon has a varying number of levels, each of which can be attained by finding and using the transporter. A key card must also be located sometimes in order to get the transporter to function. Along the way, however, are many enemies to hinder the player's progress. While fighting (or even just moving around), the mutanoid's heat level will continuously rise, until it reaches its limit. At this point, a meltdown will occur, causing the character to enter a berserk-like state. The player may continue to battle like this, but if no Cooling item is used within the time limit, the meltdown will deplete health severely.
- By meeting certain conditions in the game, players can unlock character skins for the protagonists and assume the guises of Morrigan, Lilith, Ryu, Chun-Li, Guile and Sakura.