Cowell was born in Menlo Park, California into a rural family. He was encouraged to study music by his parents, and played the violin from an early age. He began to compose in his teens, producing the piano piece The Tides of Manaunaun, which calls for the pianist to use his forearm to play many notes at once. This is one of the first uses of the tone cluster in music, and he continued to use it liberally in his later works. Despite his experimental leanings, he received no formal musical education (and little education of any kind) until he attended the University of California, Berkeley. There he studied under Charles Seeger who encouraged him to study more traditional musical subjects like harmony to compliment his experimental spirit.
In 1919 Cowell wrote and published New Musical Resources, a widely read work on the variety techniques used in his own music. Shortly thereafter he began to tour as a pianist, playing his own experimental works. Aeolian Harp (1923) is one of his first pieces for what is termed the "string piano" - rather than using the keys to play the instrument, the pianist reaches inside the instrument and plucks and scrapes the strings directly. This technique was later an inspiration to John Cage when he was developing the prepared piano.
Cowell's interest in harmonic rhythm, as discussed in New Musical Resources led him to commission Leon Theremin to invent the Rhythmicon or Polyrhythmophone, a machine capable of playing periodic rhythms in proportion to the pitches and vice versa.
Cowell subsequently began to use indeterminacy (chance) in his music more and more, though in his later works the style is rather more conservative, with simpler rhythms and a more traditional harmonic language. He began to teach and write about music more. He is often said to be instrumental in the rediscovery of Charles Ives' music, and also promoted the music of Edgar Varese. His students included John Cage, George Gershwin and Lou Harrison. He was elected to the American Institute of Arts and Letters in 1951.
Cowell died in 1965 in Shady, New York after a series of illnesses.