DePaola was born in Meriden, Connecticut to a family of Irish and Italian heritage. He had one brother, Joseph, and two sisters, Judie and Maureen. DePaola was attracted to art at an early age and credits his family with encouraging his development as an artist and influencing the themes of his works.
After high school, dePaola attended art school at the Pratt Institute in Brooklyn, New York. DePaola graduated in 1956 with a Bachelor of Fine Arts degree.
DePaola taught art at Newton College of the Sacred Heart from 1962 to 1966, then moved to California where he taught at San Francisco College for Women from 1967 to 1970. He received a Master of Fine Arts degree from California College of Arts and Crafts in Oakland in 1969, as well as a doctoral equivalency from Lone Mountain College in San Francisco. DePaola relocated to New England in the 1970s, teaching art at Chamberlayne Junior College in Boston from 1972 to 1973. From 1973 to 1976 he worked at Colby-Sawyer College in New London, New Hampshire, as an associate professor, designer, and technical director in the speech and theater department and as writer and set and costume designer for the Children's Theatre Project. He taught art at New England College in Henniker, New Hampshire, from 1976 to 1978. DePaola retired from full-time teaching in 1978 to devote his time to writing and illustrating books.
His first illustrated book was the 1965 science book, Sound.
As an actor, dePaola has appeared in several episodes of Barney & Friends as himself.
On May 18, 2009, Pratt Institute honored him with an honorary doctorate.
DePaola currently resides in New London, New Hampshire.
DePaola's awards include a 1976 Caldecott Honor for Strega Nona; a Boston Globe-Horn Book Honor in 1982 for An Old English Christmas Carol; the Golden Kite Award in 1982 for Giorgio's Village; the Aesop Award in 1994 for Christopher, the Holy Giant; the Golden Kite Award in 1987 for What the Mailman Brought; a 2000 Newbery Honor for 26 Fairmount Avenue and the 2000 Southwest Book Award from the Border Regional Library Association for Night of Las Posadas.