At this point, the player will be unable to leave the area until all enemies are defeated. In many areas where combat is initiated the first time, chains and a lock will surround the edges of the screen. Like River City Ransom, the player is free to return to previous areas, but they must complete certain battles and objectives to go to the new locations in their current area. The player progresses through six areas in a linear manner similar to Shodai Nekketsu Kōha Kunio-kun and Shin Nekketsu Kōha: Kunio-tachi no Banka.

Waves of enemies and occasional bosses are out to oppose the chosen character(s). Two players can play a local cooperative mode with both. The player can choose between Kyoko or Misako, who play similarly but have unique moves and animations.

River City Girls is a beat 'em up brawler.