While most people find the world mundane, five-year-old Yotsuba Koiwai sees it as a treasure trove of amazing bustle and wonderful places to explore. When she and her adoptive father, Yousuke, move to a new city, the energetic young girl naturally sets out to investigate the neighborhood on her own.

After a few incidents at the local park, the Koiwais become acquainted with their neighbors, the Ayase family. Their three daughters—mischievous college student Asagi, responsible high school student Fuuka, and kindhearted grade school student Ena—eventually all take a liking to Yotsuba and join in on her antics, despite their sheer ridicule.

From learning how to use a swing to figuring out how to stop global warming with air conditioners, Yotsuba's ability to infallibly find fun in everything, both amazes and annoys the people around her. Along with Yousuke, the Ayases, and friends she makes along the way, Yotsuba embarks on daily adventures, each one a step in her quest to enjoy the simple things in life.