Malipiero was born in Venice on 18 March 1882 into a family of musicians. Both his grandfather Francesco and his nephew Riccardo were composers, and his father, Luigi, was a pianist and conductor. From 1898 to 1899 Malipiero studied briefly at the Vienna Conservatory; from 1899 to 1902 he studied counterpoint with Marco Enrico Bossi at the Venice Liceo Musicale and was assistant to composer Antonio Smareglia; and in 1908 he attended Max Bruch's classes in Berlin.
Experiences which exerted a lasting influence on his creative personality were his encounter with early Italian music (Monteverdi, Frescobaldi, Merulo and others) and his stay in Paris in 1913, including his friendship with Alfredo Casella and his attendance of the première of Strawinsky's Rite of Spring which, as he later said, woke him "from a long and dangerous lethargy."
The First World War disrupted his life but, as he put it, "if I created something new in my art (formally and stylistically), it happened precisely in this period."
In the early 1920s in Rome, Malipiero joined Casella's Società Italiana di Musica Moderna, and together they founded the Corporazione delle Nuove Musiche.
From 1926 to 1942 Malipiero was active as editor of Monteverdi's complete works, and from 1939 until 1952 he was director of the Venice Liceo Musicale. As president of the Istituto Italiano Antonio Vivaldi he initiated the publication of the composer's instrumental music in 1947.
Malipiero's creative energy remained unbroken up to his death in Treviso on 1 August 1973.