River City Girls stars Kyoko and Misako, two street-tough high-schoolers who must fight their way through the six regions of River City to rescue their kidnapped boyfriends, series mainstays Kunio and Riki. Along the way, they'll utilize an arsenal of combos, counters, throws, and special attacks; battle an assortment of enemies; accept numerous side quests; level up with experience points; interact with NPCs (including guest stars from past River City games); and shop for a variety of items, food, and gear to boost stats and unlock new abilities. The girls can even wield weapons and recruit defeated foes to join them in combat!

Hot-headed Misako and her upbeat best friend Kyoko are stuck in detention at River City High when a phone photo shows their boyfriends, Kunio and Riki, apparently being kidnapped. Wasting no time, the two friends bust out and take to the streets, storming through the city in search of answers. Brawling their way past every gang, thug, and boss who stands in their way, Misako and Kyoko battle across River City to track down and rescue the two missing boys.