Manzù approached the art during the military service, held in Verona (1927 / '28), where he studied the doors of San Zeno and the casts of the Academy of Fine Arts "Giambettino Cignaroli".
Manzù went to live in Milan, where the architect Giovanni Muzio commissioned him to decorate the chapel of the Catholic University of the Sacred Heart, which will be carried out between 1931 and 1932. Also in 32 takes part in a group exhibition at the Galleria il Milione.
In 1933, he exhibited at the Milan Triennale a series of busts that earned him praise and the following year held his first major exhibition with the painter Aligi Sassu, with whom he shares the studio, at the "Cometa" gallery in Rome.
1938 he begins the series of Cardinals, an iconographic theme of his entire career. The first seated cardinal, 65 cm in height, will be exhibited at the Rome Quadriennale in 1939 together with the David, and subsequently purchased by the Galleria d'Arte Moderna in Rome.
It will produce more than 300 versions of this theme , different in size, position and materials, among these the seated Cardinal remains the most replicated and famous figure in the series.
In 1939 he began to produce a series of bronze bas-reliefs (Florentine fleck), the Depositions and the Crucifixions for the Christ series in our humanity, in which the sacred theme of the death of Jesus Christ is used to symbolize the brutality of the Fascist regime and then the horrors of war. The exhibition of the works, held in Milan in 1942, will be severely criticized by the political and ecclesiastical authorities.
In the meantime, in 1940, Manzù obtained the chair of sculpture of the Academy of Fine Arts of Brera, which will leave for dissent with the academic authorities on the study program to move to teach sculpture of the Albertina Academy in Turin. He will then leave the city with the raging of the war taking refuge in Clusone. His nude Francesca Blanc wins the 1943 Rome Quadrennial Award.
After the war he returned to teaching at the Brera Academy until 1954 and then to the Sommerakademie in Salzburg until 1960 where he met Inge Schabel, who became his life partner and with whom he had two children, Giulia and Mileto. She and her sister Sonja become the models of all her portraits.
In that period he began working, together with Alfredo Biagini, to realize the Porta della Morte for the Basilica of San Pietro in Vaticano (completed in 1964). The Vatican gate, which commits the artist from 1947 to 1964, becomes the epicenter of a poetics that, in dialogue with tradition, rejects the more strictly academic aspects.
Towards the end of the fifties, the collaboration with the MAF foundry of Milan was born with which it can create a greater number of sculptures and then expand its creations in monumental forms that are set, in 1956, on the new theme of the Mother with child; he also created the Love Gate for the Salzburg Cathedral (1955-1958).
In 1962 he took part, together with the most important international sculptors of the period, at the Sculpture exhibition in the city organized by Giovanni Carandente as part of the V Festival dei Due Mondi in Spoleto, presenting three bronze sculptures: Pattinatrice of 1958, Cardinal of 1959 and La grande key of 1959.
In 1964 Manzù went to live in a villa near Ardea (Rome), in the town of Campo del Fico in the hamlet of Fossignano adjacent to the ancient fortress of Ardea, but in the municipality of Aprilia. The town between Ardea and Aprilia has now been renamed Colle Manzù and the town of Aprilia has also dedicated its municipal library and conference room to Manzù. He created the Door of Peace and War for the church of Saint Laurens in Rotterdam (1965-1968) and, after about ten years of bas-reliefs, he returned to full-length work making bronze female figures ranging from portraits of his wife to themes more or less certainly erotic as the Artist with the model (relief), the Lovers and the Strip-tease. In 1965 the purchase of the land was completed where the Amici di Manzù Museum in Ardea will be built, at the confluence of two rivers: Fosso di Sant'Amthio, which flows into the Incastro, a legendary watercourse present in the Eneide and in the history of Rome, mentioned in the Siege of Ardea by Tarquinius the Superb.
In 1969 there is the inauguration of the Friends of Manzù Museum in Ardea. In the same year the son designer Pio dies. In the late sixties he became a stage designer, setting up costumes and scenes for Igor Stravinsky (for his Edipo Re of 1964), Goffredo Petrassi, Claude Debussy, Richard Wagner and Giuseppe Verdi. In 1968 Curtis Bill Pepper wrote about him the book An Artist And the Pope; the Pope mentioned in the title is Pope John XXIII, his countryman and personal friend; the book is translated into Italian, German, Spanish and French. Meanwhile, the fame of the sculptor comes to Japan, where in 1973 a personal exhibition was held at the Museum of Modern Art in Tokyo.
In 1979 Manzù donated his works to the Italian State.
In 1989, in New York, the last of his great achievement, a 6-meter-high bronze sculpture, was inaugurated in front of the UN headquarters. In 2007 a group of 6 sculptures was exhibited, "en plein air", in Orta S. Giulio, in the province of Novara.