Although Yannis Papaioannou studied the piano with Marika Laspopoulou and composition with Alekos Kontis at the Hellenic Conservatory, Athens (1922-34), as well as the piano and orchestration with Riadis in Thessaloniki (1928-29), he considered himself essentially self-taught, especially in 20th-century compositional techniques. In 1949 a one-year UNESCO scholarship enabled him to visit the major European music centres and to become familiar with new compositional developments; in Paris he took lessons with Honegger. For ten years (1951-61) he taught music at the aristocratic National Lyceum of Anavryta, Athens, and from 1953 he was professor of counterpoint and composition at the Hellenic Conservatory. He was the first president of both the Greek section of the ISCM (1964-75) and the Hellenic Association for Contemporary Music (1965-75).

Yannis Papaioannou exerted considerable influence as a teacher; alone in Greece before the mid-1970s in teaching atonality, 12-note and serial techniques, he numbered among his many pupils Adamis, Antoniou, Aperghis, Kounadis and Tezzakis. He acknowledged various phases in his creative career. Early impressionist (1932-38) and nationalist (1939-43) periods were followed by an interest in Hindemithian neo-classicism (as in the Suite for violin and piano or orchestra) and the use of Byzantine modes in the First Symphony. Then Papaioannou began to use 12-note (1953-62) and more recent serial procedures until in 1966 he adopted what he described as 'an entirely personal technique'. Though from the late 1950's, stimulated by the example of Skalkottas, he increasingly sought an austere and ascetic but well-wrought atonal counterpoint, his early works reveal him as a spontaneous melodist. That lyrical quality resurfaced in a few of the later works, such as Paean eis tin eirinin (1980).