The manga is about Yotsuba Koiwai, a five-year-old adopted girl who is energetic, cheerful, curious, odd, and quirky — so odd and quirky that even her own father calls her strange. At the start of the series, Yotsuba and her adoptive father, Koiwai, relocate to a new city with the help of Koiwai's best friend, an impressively tall man nicknamed "Jumbo." Yotsuba makes a strong impression on the three daughters of the neighboring Ayase family – Asagi, Fuuka, and Ena, and many of her misadventures come from her interactions with them.