In 1957 Angelillo was signed by the Italian club Internazionale by the club's president at the time, Angelo Moratti; he made his Serie A debut with the club on 8 September 1957, in a 0–0 home draw against Torino, and scored 16 goals in his first season. From 1957 to 1961, he played 127 games with the "Nerazzurri", scoring 77 times. In Serie A, he appeared in 113 matches and scored 68 goals for Internazionale, also serving as the club's captain.