Zombie Hunters puts the players in control of Aya, a Japanese cowgirl in a bikini who wears a scarf and wields a katana. Players guide their characters through the stages, completing tasks while hacking through enemies. The player-characters weapon becomes progressively covered in blood, causing their attacks to be slower and to inflict less damage, even getting stuck in enemies if it gets too bad. This is represented by a Blood Meter showing how dirty the weapon is. To prevent this, players must actively clean off their sword to keep the blood meter from filling up.

In addition, there is also the Blood Lust meter. As a character kills enemies, this meter starts to fill. Once the meter is full, the character will go into a blood frenzy. This gives the character an increase in attack power, but drains health. To recover from a blood frenzy, the player must use statue items, which are dropped by dead enemies. Additionally each level will contain a large statue. Going to the large statue will remove the blood frenzy and also recover any lost health.

Unlike the stereotypical zombies, most of the undeads encountered in this game series are not automatically killed by decapitation; some would continue to attack even after losing their upper torsoes. This is briefly explained in Zombie Hunters, Bikini Zombie Slayers by the notion that, while humans killed due to infection with bodily fluid of the undead will be zombified, most undeads are not re-animated corpses but are merely made by some supernatural power that created them to look similar to humans.