From 1965 to 1970, working with Bob Moog, the inventor of the synthesizer, Giorno produced sound and light installations he called ESPE (Electronic Sensory Poetry Environments). He electronically twisted and looped his own voice as he recited his poems and allowed audiences to step into the physical space of his poems, freeing his writing from the printed page. 

While Giorno began his career writing poetry, he recognized how the written word could be transformed into spoken word, and began a performance practice that he pursued throughout his life, pioneering a distinct and unique style. After a first performance at St. Marks Church-on-the-Bowery in 1969, Giorno performed in museums, galleries, theaters, and festivals until 2017, sometimes alongside William Burroughs and Brion Gysin. 

In 1981, he formed The John Giorno Band, with a rotating cast of musicians (Lenny Kaye on guitar, C. P. Roth on synthesizers, Paul Duggan on bass, David Donen on drums), and performed at various punk rock venues and new wave clubs including the Pyramid, Danceteria, Mudd Club, Roxy, Irving Plaza, Palladium and CBGBs.