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.

The Strega Nona Series

• Strega Nona
• Strega Nona Her Story
• Strega Nona Meets Her Match
• Strega Nona Takes a Vacation
• Strega Nona's Magic Lesson
• Brava, Strega Nona!
• Strega Nona's Harvest
• Big Anthony His Story
• Big Anthony and the Magic Ring

Memoir Series

• 26 Fairmount Avenue
• Here We All Are
• On My Way
• What a Year
• Things Will Never Be the Same (The War Years)
• I'm Still Scared (The War Years)
• Why? (The War Years)
• For the Duration (The War Years)

Big Books

• Front Porch Tales and North Country Whoppers
• Christmas Remembered
• Tomie dePaola's Big Book of Favorite Legends
• Tomie dePaola's Book of Bible Stories
• Tomie dePaola's Favorite Nursery Tales
• Tomie dePaola's Mother Goose

Tomie's Stories about Growing Up and His Family

• The Art Lesson
• The Baby Sister
• Nana Upstairs & Nana Downstairs
• Stagestruck
• Tom
• Tony's Bread
• Watch Out for Chick Feet in Your Soup

Books of Legends, Folktales and Stories

• Adelita A Mexican Cinderella Story
• Andy That's My Name
• Charlie Needs a Cloak
• The Cloud Book
• Comic Adventures of Old Mother Hubbard
• Cookie's Week
• Days of the Blackbird
• Erandi's Brainds
• Fin M'Coul
• Four Friends at Christmas
• Four Friends in Autumn
• Four Friends in Summer
• Four Stories for Four Seasons
• Hey Diddle Diddle and Other Mother Goose Rhymes
• Hunter and the Animals
• I Love You, Mouse
• Jamie O'Rourke and the Big Potato
• Jamie O'Rourke and the Pooka
• Knight and the Dragon
• Legend of the Bluebonnet
• Legend of the Indian Paintbrush
• Legend of the Persian Carpet
• Little Grunt and the Big Egg
• Mice Squeak We Speak
• Mr. Satie and the Great Art Contest
• Mysterious Giant of Barletta
• Now One Foot, Now the Other
• Oliver Button is a Sissy
• Pancakes for Breakfast
• The Popcorn Book
• The Quicksand Book
• The Quilt Story
• Frida Kahlo
• Shh, We're Writing the Constitution
• T-Rex Is Missing
• The Tale of Rabbit and Coyote

Books of Religious or Holiday Stories

• Angels Angels Everywhere
• Christopher the Holy Giant
• The Clown of God
• Francis Poor Man of Assisi
• Get Dressed Santa
• Guess Who's Coming to Santa's for Dinner?
• The Holy Twins
• Legend of Old Befana An Italian Christmas Story
• Legend of the Poinsettia
• Miracles of Jesus
• My First Chanukah
• My First Christmas
• My First Easter
• My First Halloween
• My First Passover
• My First Thanksgiving
• The Night before Christmas
• Night of Las Posadas
• Parables of Jesus
• Pascual and the Kitchen Angels
• Patrick Patron Saint of Ireland
• The Song of Francis
• Tomie's Little Christmas Pagent
• An Old English Christmas Carol

The Bill and Pete Books

• Bill and Pete
• Bill and Pete Go Down the Nile
• Bill and Pete to the Rescue

The Barkers

• Boss for a Day
• Hide and Seek All Week
• Meet the Barkers
• Morgan and Moffat Go to School
• A New Barker in the House
• Trouble in the Barker's Class

Board Books for the Very Young

• I Love You Sun, I Love You Moon
• Marcos Counts
• Mary Had a Little Lamb
• Mice Squeak We Speak
• Tomie's Little Book of Love
• Tomie's Baa Baa Black Sheep
• Tomie's Little Book of Poems
• Tomie's Little Mother Goose
• Tolmie's Mother Goose Flies Again
• Tomie's Three Bears and Other Tales

Video (in DVD format)

• Tomie Live in Concert