He married Nora Maffi, the daughter of Fabrizio Maffi, a founder of the Italian Communist Party, and they had two sons, Louis and Paolo, grandchildren Pippo and Annie and Sylvan, and great-grandchildren Madeline, Luca, Sam, Nick, Alix, Henry and Theo.

In 1939, he moved to Philadelphia and began full-time work in advertising, at which he was extremely successful, acquiring accounts from Ford Motors and Chrysler Plymouth, among others.

He commissioned art from Saul Steinberg, the then neophyte Andy Warhol, Alexander Calder, Willem de Kooning, and Fernand Léger.

Over the course of his career, Lionni also held several teaching posts, beginning in 1946, when he taught advertising art at Black Mountain College.

Many of Lionni's books deal with issues of community and creativity, and the existential condition, rendered as fables which appealed to children.

Lionni uses earth tones in his illustrations that are close to the actual colors of the objects found in nature.

Lionni's illustrations have been compared to those of Eric Carle as both often employ animals, birds, insects, and other creatures to tell a story about what it is to be human.

[5] Among Lionni's books that were not intended for children, the best known is probably Parallel Botany (1978; first published in Italian as La botanica parallela, 1976).

The text is a rich mix of plant descriptions, travel tales, "ancient" myths, and folk etymologies, leavened with historical facts and grounded in actual science.