Wainwright was born in Chapel Hill, North Carolina, the son of Martha Taylor, a yoga teacher, and Loudon Wainwright, Jr., a columnist and editor for Life magazine. Wainwright grew up in Bedford, New York, in Westchester County. Among his sisters is Sloan Wainwright, also a singer. He graduated from St. Andrew's School in Delaware. He is a direct descendant of Peter Stuyvesant, the last Director-General of New Netherland (present-day New York City).
Wainwright's career began in the late 1960s. He had played the guitar while in school, but would later sell it for yoga lessons while living in San Francisco. Later, in Rhode Island, Wainwright's grandmother got him a job working in a boatyard. An old lobsterman named Edgar inspired him to borrow a friend's guitar and write his first song, "Edgar". Wainwright soon bought his own guitar and in about a year wrote nearly twenty songs. He went to Boston and New York to play in folk clubs and was eventually "discovered" by Milton Kramer who became his manager. He acquired a record deal with Atlantic Records, who released his first album in 1970.
Wainwright is perhaps best known for the 1972 novelty song hit, "Dead Skunk (in the Middle of the Road)", and for playing Captain Calvin Spalding (the "singing surgeon") on the American television show, M*A*S*H. His appearances spanned three episodes in its third season (1974-1975), including the episode "Rainbow Bridge". However, his musical reputation is much deeper. Using a witty, self-mocking style, Wainwright has recorded over twenty albums on eleven different labels. Two of his albums have been nominated for Grammy awards: I'm Alright (1985) and More Love Songs (1986).
Wainwright has also appeared in a number of films, including small parts in The Aviator, Big Fish, Elizabethtown, The 40-Year-Old Virgin, Knocked Up and the television series, Undeclared. Wainwright came to the attention of many people in Britain for the first time when he appeared as the resident singer with comedian Jasper Carrott in his UK show, Carrott Confidential, in the late 1980s, and he has remained popular in the UK ever since.
He appeared a musical guest on Saturday Night Live on the 5th episode it was broadcasted, on November 15, 1975. He performed the songs "Bicentennial" and "Unrequited to the Nth Degree" as a guest to Robert Klein.
Wainwright has claimed that, like many of his contemporaries, he was inspired musically by seeing Bob Dylan at the Newport Folk Festival in 1962. He was one of many young folksingers tagged as the "new Dylan" in the early 1970s, a fact that he later ruefully satirized in his song, "Talking New Bob Dylan", from History (1992).
Wainwright was also a judge for the 4th annual Independent Music Awards.
According to his own liner notes, Wainwright entered a period of deep depression following the death of his mother in 1997, and believed he could never write again. Retreating to his mother's cabin in the woods, he underwent therapy and gradually recovered, eventually recording the soul-baring Last Man on Earth in 2001. Since then his recording career has mostly returned to its previous frequency.
In September 2006, Wainwright and musician Joe Henry began composing the music to the Judd Apatow film, Knocked Up, which was released on June 1, 2007. In addition to composing the soundtrack, Wainwright appeared in the film in a supporting role as the protagonists' obstetrician. He has also composed music for the new theatre production of Carl Hiassen's Lucky You, which premiered at the 2008 Edinburgh Festival Fringe.
Wainwright's son, Rufus Wainwright, and daughter, Martha Wainwright, from his former wife Canadian singer/songwriter Kate McGarrigle are both singer/songwriters as well. Rufus was the subject of two of Loudon's more famous songs, the breastfeeding ode "Rufus is a Tit Man" and the retrospective "A Father and a Son", while Martha entered the world to "Pretty Little Martha", turned five to the post-divorce child-rearing anthem "Five Years Old" and entered her teenage years with the brutally clinical "Hitting You". Rufus, in turn, has covered his father's "One Man Guy" and wrote "Dinner at Eight" about a family dispute, while Martha has covered her father's "Pretty Good Day" and wryly states that her song, "Bloody Mother Fucking Asshole", is about her father. On the other hand, Martha and Loudon collaborated on the song "You Never Phone" on his 2003 album, So Damn Happy. Martha also duets with Loudon on 'Father Daughter Dialogue' from Grown Man (1995).
Loudon also has a daughter, Lucy Wainwright Roche, with singer Suzzy Roche, and a third daughter, Lexie Kelly. Loudon remarried in 2005.