Newsom was first taught to play the Celtic harp by a local teacher in Nevada City. Later on she moved on to the pedal harp and started composing.
Newsom studied composition and creative writing at Mills College, Oakland, California.
After touring with Will Oldham, she was quickly signed to Drag City and released her debut album The Milk-Eyed Mender in 2004. Shortly thereafter, Newsom toured with Devendra Banhart and Vetiver and made an early UK appearance at the Green Man Festival in Wales, returning to headline in 2005 and 2007, respectively.
Newsom's work has become prominent on the indie scene, and her profile has risen, in part due to a number of live shows and appearances on Jimmy Kimmel Live on ABC.
Her second album Ys was released in November 2006. The album features orchestrations and arrangements by Van Dyke Parks, engineering from Steve Albini, and mixing by Drag City label-mate Jim O'Rourke. On a road trip, Bill Callahan recommended she listen to the album Song Cycle by Parks, which led to his being chosen to arrange her work on Ys.
Having sporadically debuted new songs at her concerts since the fall of 2007, on March 28, 2009, Newsom performed over two hours of new material at a "secret" concert in Big Sur, California with fellow Nevada City singer-songwriter Mariee Sioux, under the pseudonym The Beatles's. Those in attendance reported that about one-third of her new material was played primarily on piano, with a backing arrangement of banjo, violin, guitar and drums. Furthering speculation on her third release, Drag City also hinted of a "big release" planned for sometime in September.
Several of the songs on The Milk-Eyed Mender have been covered by her peers: "Bridges and Balloons" was covered by the Decemberists on their 2005 EP Picaresqueties. "Sprout and the Bean" has been covered by The Moscow Coup Attempt and Sholi. "Peach Plum Pear" has been covered by Final Fantasy (Owen Pallett) on the 2006 EP Young Canadian Mothers, as well as by Straylight Run. M Ward has played "Sadie" on his live shows.
In 2009, she appeared in the music video for the song "Kids" by the alternative dance group MGMT.
Although her harp playing is not completely divorced from conventional harp techniques, she considers her style distinct from that of classically focused harpists. For instance, she has been strongly influenced by polyrhythms, used by West African kora players. Her harp teacher, Diana Stork, taught her the basic pattern of four beats against three, which creates an interlocking, shifting pattern that can be heard on Ys, particularly in the middle section of "Sawdust & Diamonds."
The media have sometimes labeled her as one of the most prominent members of the modern psych folk movement, although she does not acknowledge ties to any particular musical scene. Her songwriting incorporates elements of Appalachian music, avant-garde modernism, and African kora rhythms.
Newsom's vocal style (in the November 2006 issue of The Wire she described her voice as "untrainable") has shadings of folk and appalachian shaped-note timbres. Newsom has, however, expressed disappointment at comments that her singing is "child-like."
Alongside her solo material she has played on records by Smog, Vetiver, Nervous Cop, The Year Zero, Vashti Bunyan, Moore Brothers, Sydney Symphony Orchestra and Golden Shoulders and played keyboards for The Pleased.
Newsom's family includes her brother Pete, a fellow musician, and sister Emily, an astrophysicist who inspired her song "Emily" (and contributed backing vocals). Her 2nd cousin (once removed), Gavin Newsom, is currently the mayor of San Francisco.