The player assumes the role of Chris, the protagonist of Popotan. Chris is a high school dropout who dislikes the direction of society and refuses to get a job. He wanders the streets making a living as a guitar-playing busker. He feels he cannot play well without an audience, which is hard to find as a drifter. The other main characters include three sisters and their maid who live in a western-style mansion. Ai is the eldest of the three and communicates with plants. Mai is the middle sister; she is a tomboy and disapproves of Chris's behavior. Mii is the youngest and the most energetic; she often cosplays as "Magical Girl Mii" and helps people. Their maid Mea appears emotionless at first, but reveals hidden depth later in the story.
Popotan takes place in the distant future within the remnants of Tokyo, destroyed by a cataclysm and since altered by geological transformations. The disaster was caused by a giant dandelion structure resembling a spire that arose in the city atop a hill. The main location of the game is a European-style mansion, seen as completely out-of-place in the city. Much of the daytime is spent outside the mansion wandering around town meeting characters and triggering event sequences.
Popotan follows Chris's lifestyle changes, as well as the mysteries surrounding the spire-like object that caused the destruction of Tokyo in the past. The story opens as Chris desperately considers stealing food from a stand near a shrine entrance. His theft is unsuccessful, and he wanders around town looking for work. He finds a convenience store, where he gets directions leading him to the mansion. He enters without asking permission and runs into the three sisters and their lifelike android maid. Chris asks permission to stay because the rent is cheap and the girls are pretty; they consent, but force him to take a part-time job. The convenience store owner hires him, and as the story progresses, Chris opens up socially and begins caring about others as he interacts with the girls. He also meets new friends, including a classmate Konami, a local shrine maiden named Nono and a mysterious girl named Shizuku.