Mamma Santa's was established by Guido and Nancy Scaffidi July 25, 1961. Before launching the restaurant, Guido worked as an auto body repair man and Nancy as a hair dresser. Guido served in World War II and was a prisoner of war. Shortly after World War II, Guido and Nancy emigrated from Gioiosa Marea, Sicily and settled in Akron before moving to Cleveland's Little Italy.

Mamma Santa's has been in the same location since its inception. The building is more than 100 years old and was used as a bank, clothing store and a cafe before ultimately becoming Mamma Santa's.

The restaurant is named in honor of Nancy's mother, Santa Ignazzito, who was born on All Saints Day, November 1, 1908. Santa used her recipes straight from Sicily to create the authentic Sicilian menu.

Guido and Nancy's sons, Anthony and Danny, began working at the restaurant as teenagers. They have overseen the daily operation of the restaurant since Guido retired in 1996. Today, the restaurant remains a family operation; Anthony's wife Pina makes all of the homemade pastas, sauces, and dough for the restaurant daily. Anthony's four children all work at the restaurant, as well.