D'Onofrio was born in Bensonhurst, Brooklyn. He is of Italian descent, with ancestors from Naples. His parents, Gennaro and Phyllis D'Onofrio, an interior designer/theater-production assistant, and server, respectively, met while Gennaro was stationed in Hawaii with the U. S. Air Force. In 1956, they had their first child, Antoinette. Their second child, Elizabeth (born 1957), is an actress and drama coach residing in Fort Myers Beach, Florida, and then Vincent was born, the youngest of the three siblings. He was raised in Hawaii and Colorado during his early years.