In 1987, Everett moved from his family home in Virginia and resettled in California. There, Everett began his professional musical career with two major-label albums: A Man Called E and Broken Toy Shop. The pseudonym "E" was used for both of these early recordings. He became known as "E" because there were several people in his life at the time who had the same first name. While it may have caused some confusion in record stores and radio stations, the single-letter name gave the press a playful handle. This playfulness was evident in a review by the eminent Writer Daniel Levitin which began: "Excellent eponymous effort, energizingly eclectic. Early enthusiasm effectively ensures E's eminence." A Billboard magazine review of his second album was similarly positive.

Everett's father, Hugh, died of heart failure when Everett was 19. Mark was the one to find him. His sister, Elizabeth, committed suicide in 1996, and in 1998 his mother, Nancy Everett née Gore, died of lung cancer. Following these tragedies, Everett and the Eels released Electro-Shock Blues in 1998.

Everett has used everything from a toy piano in his early "Symphony for a Toy Piano in G Minor" to hammers on a radiator as percussion in 1998's "Cancer for the Cure". Despite his constant denials, he is suspected of being the man behind MC Honky, who released the album I Am the Messiah in 2003.

In 2000 he married Natalia Kovaleva, a Russian dentist he met near Hamburg, Germany. The marriage ended after five years. Following the EELS' tour accompanying their eleventh studio album The Cautionary Tales of Mark Oliver Everett, Everett took a break from music. During this period, he met a Scottish woman employed in the film industry. At the age of 54, Everett became a father for the first time, his then-wife having given birth to their son, Archie McGregor Everett. The couple, however, divorced some time later.

His cousin, Jennifer Lewis née Gore, was a FLIGHT attendant on the plane that struck The Pentagon during the September 11, 2001 attacks. The plane struck the side of the Pentagon where his father had worked, and Everett remarks in his autobiography that he wonders whether the plane hit his father's old office.

During 2005, Everett and his ad hoc Eels went on tour promoting his album, Blinking Lights and Other Revelations. It was during this recording that he worked with long-time hero and influence Tom Waits. In November 2007, Everett published his autobiography, entitled Things the Grandchildren Should Know.

The 2007 BBC Scotland / BBC Four television documentary "Parallel Worlds, Parallel Lives", followed Everett as he talked to physicists and his father's former colleagues about his father's theory. The documentary won a Royal Television Society award on March 19, 2008. The documentary was shown in lieu of a support act during their UK, US, Irish and Australian tours in the spring of 2008. In the U.S., the PBS program Nova broadcast the documentary in October 2008.

The seventh Eels studio album—Hombre Lobo: 12 Songs of Desire—was released on June 2, 2009.

On January 19, 2010, Everett released his eighth Eels album, entitled End Times, which deals with themes of aging and divorce. On August 23, 2010, Eels released a 9th album, 'Tomorrow Morning', which represents the final part of the trilogy begun by 'Hombre Lobo.'

On February 4, 2013, the tenth album of Eels, Wonderful, Glorious, was released, followed by The Cautionary Tales Of Mark Oliver Everett, released only a year later on April 21, 2014.

In July 2014 Everett was given the Freedom of the City of London, at a ceremony held prior to his concert at the Barbican Centre.

On February 19, 2016, Everett appeared as Brian in Series 1 Episode 4 (A Party In The Hills) of Judd Apatow's Love, playing a cover of Paul McCartney's song 'Jet.' He also briefly appeared in Series 1 Episode 9, Series 2 Episode 2 and Series 3 Episode 6.

The twelfth Eels album, The Deconstruction, was released on April 6, 2018.