Sinéad O'Connor was born in Dublin and was named after Sinéad de Valera, wife of Irish President Éamon de Valera and mother of the doctor presiding over the delivery, and Saint Bernadette of Lourdes. She is the middle of five children. Her parents separated when Sinéad was eight. The three eldest children went to live with their mother, where O'Connor claims they were subjected to frequent physical abuse. Her song "Fire on Babylon" is about the effects of her own child abuse, and she has consistently advocated on behalf of abused children.

In 1979, O'Connor left her mother and went to live with her father and his new wife. However, her shoplifting and truancy led to her being placed in a reform school at age 15. In some ways, she thrived there, especially in writing and music, but she also chafed under the imposed conformity.

In 1983, her father sent her to Newtown School, an exclusive Quaker boarding school in Waterford. With the help and encouragement of her Irish language teacher, Joseph Falvey, she recorded a four-song demo, with two covers and two of her own songs which would later appear on her first album.

Through an ad she placed in Hot Press in the summer of 1984, she met Columb Farrelly. Together they recruited a few other members and formed a band called Ton Ton Macoute, named for the zombies of Haitian myth. In the autumn, the band moved to Waterford briefly while O'Connor attended Newtown, but she soon dropped out of school and followed them to Dublin, where their performances received positive reviews. Their sound was inspired by Farrelly's interest in witchcraft, mysticism, and world music, though most observers thought O'Connor's singing and stage presence was the band's driving force.

On February 10, 1985, O'Connor's mother was killed in an automobile accident. O'Connor was devastated despite her strained relationship with her mother. Soon afterward she left the band, which stayed together despite O'Connor's statements to the contrary in later interviews, and moved to London.

O'Connor's time as singer for Ton Ton Macoute brought her to the attention of the music industry, and she was eventually signed by Ensign Records. O'Connor's first two albums (1987's The Lion and the Cobra and 1990's I Do Not Want What I Haven't Got) gained considerable attention and mostly positive reviews. She was praised for her voice and her original songs. She was also noted for her appearance: her shaved head, often angry expression, and sometimes shapeless or unusual clothing.

The Lion and the Cobra was not embraced by the pop mainstream on a large-scale basis, but the album did eventually hit gold record status and earned a Best Female Rock Vocal Performance Grammy nomination. The single "Mandinka" was a big college radio hit, and "I Want Your (Hands on Me)" received both college and urban play in a remixed form that featured rapper MC Lyte.

I Do Not Want What I Haven't Got contained her international breakthrough hit "Nothing Compares 2 U", a song written by Prince and originally recorded and released by a side project of his, The Family. Aided by a memorable and well received video by John Maybury which consisted almost solely of O'Connor's face as she performed the song, it became a massive international hit, reaching #1 in several countries. In Ireland it hit the top spot in July 1990 and remained there for 11 weeks; it is the eighth most successful single of the decade there. It had similar success in the UK, charting at #1 for three weeks, and in Germany (#1 for 11 weeks). In Australia, it reached #1 on the Top 100. It also claimed the #1 spot on the Hot 100 chart in the USA. She also received Grammy nominations including Record of the Year and Best Female Pop Vocal Performance. She eventually won the Grammy for Best Alternative Music Performance, but boycotted the award show.

After spending nine years dividing her time between London and Los Angeles, O'Connor returned to her home town of Dublin in late 1992 to live near her sister and focus on raising her son Jake, then six years old. She spent the following months studying Bel Canto singing with teacher Frank Merriman at the Parnell School of Music.

Faith and Courage was released in 2000, including the single "No Man's Woman," and featured contributions from Wyclef Jeanof the Fugees and Dave Stewart of Eurythmics. Her 2002 album, Sean-Nós Nua, marked a departure in that O'Connor interpreted or, in her own words, "sexed up" traditional Irish folk songs, including several in the Irish language.

She has been nominated in the Best Irish Female category for Ireland's celebrated Meteor Awards 2008.