Parker grew up in the South Bronx section of New York City to parents of Nigerian and Jamaican descent. In his teenage years, he frequently accompanied the Hare Krishnas and was susbsequently nicknamed "Krisna", hence "Kris". "KRS-One" was originally Parker's graffiti tag, short for "Kris Number One". He began using it as his stage name and later devised a backronym for the name: "Knowledge Reigns Supreme Over Nearly Everyone."

After four largely solo albums under the name "Boogie Down Productions," KRS-One decided to strike out on his own. On his first solo album, 1993's Return of the Boom Bap, Parker worked together with producers DJ Premier, Kid Capri and Showbiz, the latter providing the catchy-yet-hardcore track "Sound of da Police". His second album, 1995's KRS-One, featured Channel Live on "Free Mumia", a protest song about the persecution of Mumia Abu-Jamal, a Black Panther facing a controversial death row sentence, and the persecution of hip hop by C. Delores Tucker. Other prominent guest stars on KRS One included Mad Lion, Busta Rhymes, Das EFX and Fat Joe.

In 1997, Parker surprised many with his release of the album I Got Next. The album's lead single "Step into a World (Rapture's Delight)", containing a sample of punk and New Wave group Blondie, was accompanied by a remix featuring commercial rap icon Puff Daddy; another track was essentially a rock song. While the record would be his best-selling solo album (reaching #3 on the Billboard 200), such collaborations with notably mainstream artists and prominent, easily recognizable samples took many fans and observers of the vehemently anti-mainstream KRS-One by surprise. However, in August 1997, Parker appeared on Tim Westwood's BBC Radio 1 show and vociferously denounced the DJ and the radio station more generally, accusing them of ignoring his style of hip hop in favor of commercial artists such as Puff Daddy. In 1999, there were tentative plans to release an album called Maximum Strength; a lead single, "5 Boroughs", was released on The Corruptor movie soundtrack. However, Parker apparently decided to abort the album's planned release, just as he had secured a position as a Vice-President of A&R at Reprise Records. He moved to southern California, and stayed there for two years, ending his relationship with Jive Records with A Retrospective in 2000.

Parker resigned from his A&R position at Reprise in 2001, and returned to recording with a string of albums, beginning with 2001's The Sneak Attack on Koch Records. In 2002, he released a gospel-rap album, Spiritual Minded, surprising many longtime fans; Parker had once denounced Christianity as a "slavemaster religion" which African-Americans should not follow. During this period, KRS founded the Temple of Hiphop, an organization to preserve and promote "Hiphop Kulture". Other releases have since included 2003's Kristyles and D.I.G.I.T.A.L., 2004's Keep Right, and 2006's Life.