Partch was born in Oakland, California. Both his parents were Presbyterian missionaries. He learnt to play the clarinet and guitar as a child, and there was also a harmonium in the house, which he played. He began to compose at an early age using the chromatic scale normal in western music, but burned all his early works after becoming frustrated with what he saw as the imprefections of that particular system of musical tuning.
Eventually, he divised his 43 note scale and built an adapted viola to play music in it. He secured a grant, which allowed him to go to London to study the history of tuning systems. While there, he met the poet W. B. Yeats with the intention of gaining his permission to write an opera based on his translation of Sophocles' Oedipus the King. He took another instrument he had built, an adapted guitar, to the meeting, and accompanied himself in one of his own songs on it. Yeats was enthusiastic, saying "a play done entirely in this way, with this wonderful instrument, and with this type of music, might really be sensational", and giving Partch's idea his blessing.
Partch set about building more instruments with which to realise his opera. However, his grant money ran out, and, back in the United States, he began to live as a hobo, travelling around on trains and taking casual work where he could find it. He continued in this way for ten years, writing about his experiences all the time in journals which were later collected together under the title Bitter Music. They frequently include snatches of overheard speech notated on musical staves according to the pitcheses used by the speaker. This technique (which had been earlier used by Leos Janacek and would be later used by Steve Reich) was to become a standard approach to the writing of vocal parts in Partch's work.
In 1941, Partch wrote Barstow, a vocal piece which takes as its text eight pieces of graffiti he had seen on a highway railing in Barstow, California. The piece uses his 43 note scale, and is scored for his custom built instruments.
In 1943, Partch received another grant, and was able to settle down somewhat, and work with more dedication on the music that interested him. He returned to his Oedipus project, although the executors of Yeats' estate refused permission for him to use Yeats' translation, and he had to make his own (a recording with Yeats' translation has since been released, Yeats' text having passed into the public domain). He also started work on US Highball, a piece which used many of his jottings from his hobo years as text. The work is, essentially, the story of a hobo's trip from Oakland, California to Chicago, a journey which Partch had himself undertaken.
Around this time, Partch was also working on a book, eventually published as Genesis of a Music. It is an account of his own music, with sections on the scale he uses and the instruments he built. It has served as an inspiration for many microtonal composers who followed him.
Partch went on to write The Bewitched, a sort of cross between a ballet and an opera and Revelation in the Courthouse Park, a work based in large part on Euripides' The Bacchae. Delusion of the Fury (1969) is seen by some as his greatest work. He died in San Diego, California of a heart attack.
Partch was never very well known, but he set up his own record label, "Gate 5", to release recordings of his works. Towards the end of his life, Columbia Records made recordings of some of his works, including Delusion of the Fury, which helped in large part to bring him to the attention of the musical world. He remains a somewhat obscure figure, but is well known in experimental and microtonal circles, and possibly the most important and influential microtonal composer of them all.