Mushihimesama is a vertically scrolling shooter; players need to control their character over the constantly scrolling terrain and score points by shooting the various enemies that appear. Each of the five stages ends with a large "boss" battle. Like other games from developer CAVE, Mushihimesama is a "bullet hell" style shooter; the numerous opponents you encounter fire a very significant number of bullets, often completely covering the entire playfield. The player will need to either dodge these by navigating through the complex pattern formed or by utilising the shield that is available for a limited time. As is typical for arcade style shooters, weapon upgrades are available to make blasting enemies easier.
Mushihimesama features three difficulty levels, original arcade, maniac, and ultra. In addition to these three modes found in the original arcade version, the PS2 version also adds a practice mode where any stage and boss battle can be practiced as well as the arrange mode. In arrange mode, the player begins fully equipped with weapon upgrades and changes are made to the scoring system.