He started working with wood during his military service in Verona in 1928; later, after a short stay in Paris, he moved to Milan, where architect Giovanni Muzio commissioned him the decoration of the chapel of Università Cattolica del Sacro Cuore (1931–1932).
In 1939 Manzù started a series of bronze bas-reliefs about the death of Jesus Christ; the works, exhibited in Rome in 1942, were criticized by the Fascist government and the ecclesiastical authorities.
He created two sculptures in stiacciato relief at Rockefeller Center on the former Italian building in the 1960s, one titled "The Immigrant" and the other "A Fruitful Harvest".
Tasende Gallery inaugurated their first location in La Jolla, California on 1 June 1979 with a solo presentation of Manzu's work, attended by his wife Inge.
In the United States, architect Minoru Yamasaki commissioned him the Passo di Danza (dance step) sculpture at the One Woodward Avenue building in Detroit.