Nono began his musical studies in 1941 at the Venice Conservatory. He then studied law at the University of Padua, receiving a doctorate there, while at the same time studying with the prominent avant-garde composer Bruno Maderna (Maderna, Bruno) and the noted conductor Hermann Scherchen (Scherchen, Hermann). He came to public attention in 1950 with his work Variazioni Canoniche, orchestral variations on a 12-tone theme of Arnold Schoenberg (Schoenberg, Arnold), whose daughter Nuria he married in 1955. He continued to explore avant-garde techniques and lectured widely in Europe and the United States. He also taught at the New Music Summer School at the Kranichsteiner Music Institute in Darmstadt, Ger..

Nono's music is distinguished by its clarity of form. Polyphony (simultaneous melodic lines), monophony (melody without harmony), and rhythm are explored in a straightforward manner in his Polifonica-monodia-ritmica for seven instruments (1951). The Suspended Song (1955–56), a serial setting for voices, chorus, and orchestra of letters written by victims of Nazism, passes its melody among the instruments and voices with each performer rarely playing more than a single note at a time. Nono also adopted this technique of fragmentation in several works involving voices and percussion. Per Bastiana Tai-yang Cheng (1967), based on a Chinese folk song and celebrating the birth of the Nonos' daughter, is somewhat aleatoric and calls for three instrumental groups playing in quarter tones and for magnetic tape.

An avowed Communist, Nono often produced works of political substance, many of which sparked controversy and reaction. When his opera Intolleranza 1960, which Nono referred to as a “mural,” premiered in Venice in 1961, the performance was stormed by neofascists, causing a riot with the communists. The work attacked fascism, the atom bomb, and segregation and ended in a symbolic fashion in which the world is flooded and destroyed. The opera was later revised as Intolleranza 1970.

La Scala in Milan commissioned a new opera from Nono in the early 1970s. Al Gran Sole Carico d'Amore (1972–75; “In the Great Sun of Blooming Love”) took its title from a poem by Arthur Rimbaud (Rimbaud, Arthur), “Les Mains de Jeanne-Marie,” and is about the Paris Commune of 1871. Its theme was devoted to the class struggle, with no conventional plot or characters, and showed the influence of Arnold Schoenberg's pre-World War I Expressionism. The opera did not, however, premier at La Scala but at Teatro Lirico. La Scala produced a revised version in 1978.

Nono was greatly inspired by the Spanish poet Federico García Lorca (García Lorca, Federico) and wrote Der Rote Mantel (1954; “The Red Overcoat”) based on one of his poems. His Epitaffio per Federico García Lorca (1952) was hailed as a major work and is a set of three pieces in memory of Lorca. Other politically inspired works include the dramatic cantata Sul ponte di Hiroshima (1962; “On the Bridge of Hiroshima”), dealing with the implications of nuclear warfare; Ein Gespenst geht um in der Welt (1971; “A Spirit Haunts the World”), a setting for voice and orchestra of The Communist Manifesto; and Canto per il Vietnam (1973; “A Song for Vietnam”). A longtime member of the Italian Communist Party, Nono was elected to its Central Committee in 1975 and remained a member until his death. His later works include A Pierre: Dell'azzurro silenzio, inquietum for bass flute, contrabass clarinet, and live electronics (1985) and No hay caminos, hay que caminar, a tribute to the director Andrey Tarkovsky, for orchestra (1987).