Mushihimetama is a pseudo sequel to Puzzle Uo Poko, shifting the setting to Cave's popular game Mushihimesama and featuring its heroine Reco. It follows basically the same gameplay, with a new twist: each level features one of Reco's insect friends trapped underneath layers of coloured balls. Reco's goal isn't to eliminate all of the balls in the stage, but just to clear enough of them so that her friend can escape. Like Uo Poko, there is a two-player cooperative mode, and new to this game is a competitive mode in which two players compete to be the last player standing in an endlessly-growing puzzle field.
Like Uo Poko, Mushihimetama came with special ball tops themed after Reco's insect friends; these can be screwed into a standard arcade joystick to replace the original ball top.