The story begins with the birth of an exceptionally small mouse, who is the only one of his litter to survive. The lone mouse is born to a French mouse named Antoinette, who declares the birth a “disappointment.” Thus, young Despereaux receives his name “for all the sadness, for the many despairs in this place” (12). Despereaux’s older siblings remark on his large ears and open eyes—unusual for a newborn mouse. The children’s father, Lester, assumes something is wrong with Despereaux because he is looking directly at the sun reflecting “onto the ceiling in an oval of brilliance” (13). Antoinette swears off having more children because they “ruin” her looks, and Lester assumes Despereaux will die from frailty. The narrator, however, foreshadows that he will live.

Despereaux Tilling lives beyond his first few days to everyone’s surprise, and he quickly becomes the talk of the mouse community. His aunts and uncles observe his ears and the small size of his body, doubting his being born with open eyes because such a thing is “impossible” for a mouse. Despereaux carries a handkerchief due to his sickly demeanor, and he behaves differently from other mice: He obsesses over music and sunlight rather than crumbs of cake.