"Mouse Bakumatsu-den" is set during the Bakumatsu period in Japan, a time of significant political upheaval and social change as the Tokugawa shogunate nears its end. The story centers on Mouse, a skilled and enigmatic swordsman with a mysterious past. Mouse is a ronin, a masterless samurai, who roams the land with a unique sense of justice and a penchant for getting involved in conflicts that expose the corruption and moral decay of the era.

The narrative unfolds as Mouse encounters various factions vying for power, including loyalists to the shogunate, imperial restorationists, and foreign forces seeking to exploit Japan's instability. Mouse's journey is marked by a series of battles, alliances, and betrayals, as he navigates a world where loyalty is fluid and survival often depends on cunning and skill. His actions frequently place him at odds with powerful figures, including corrupt officials, ruthless mercenaries, and ambitious revolutionaries.

Key characters include Shizuku, a determined young woman with her own agenda tied to the political turmoil, and Ryoma Sakamoto, a historical figure reimagined in the story as a charismatic revolutionary who crosses paths with Mouse. Their interactions highlight the tension between personal ideals and the harsh realities of a society in transition. The series also features a diverse cast of supporting characters, each representing different facets of the era's struggles, from impoverished peasants to disillusioned samurai.

The plot is driven by Mouse's quest for redemption and his struggle to reconcile his violent past with his desire to protect the innocent. As the story progresses, it delves into themes of honor, sacrifice, and the cost of revolution, set against the backdrop of a nation on the brink of transformation. The manga combines historical elements with fictionalized drama, creating a vivid portrayal of a pivotal moment in Japanese history.