Murs formed 3 Melancholy Gypsys with fellow Alexander Hamilton High School classmates Scarub and Eligh. The group became friends with Mystik Journeymen, and joined them in the Living Legends collective in 1996. His solo debut album, F'Real, was released on Veritech in 1997.

Alongside Slug, Murs has been part of the group Felt since 2002. The End of the Beginning, his debut album on Definitive Jux, was released in 2003. Murs released Murs 3:16: The 9th Edition, an album entirely produced by 9th Wonder, in 2004. Taking a more thoughtful approach than gangster rappers, it prompted Andy Gill of The Independent to say "eschewing bogus glamour for emotional realism, Murs manages to say more about the corrosive cancer of hip-hop's gun culture than all the thousands of column inches lavished on 50 Cent's bullet wounds". After another collaborative album with 9th Wonder, Murray's Revenge, in 2006, Murs signed a contract with Warner Bros., his debut album for the label being Murs for President. It was preceded by Sweet Lord which was given away free to fans.

Murs released Varsity Blues 2, a follow-up to his Varsity Blues EP, with production duties handled by Aesop Rock, Terrace Martin and Droop-E in 2011. He released This Generation, a collaborative album with Fashawn, in 2012.

Murs was invited by Sacha Jenkins, a hip hop journalist, to join the group The White Mandingos, a collaboration between Jenkins and Bad Brains bassist Daryl Jenifer. They released their first album, The Ghetto is Tryna Kill Me, on June 11, 2013 under the Fat Beats record label. Murs has stated that the recording is a loose concept album about a man from the hood who struggles to maintain his identity while recording as a rock artist. The band members have acknowledged that the album is partially based on their own experiences.

On February 7, 2014, it was announced via Tech N9ne's Facebook page that Murs was signed to his record label Strange Music. Later that year, Murs teamed up with fellow Strange Music members Mayday! to drop the !Mursday¡ album as his first release on the label. He then released Have a Nice Life on May 18, 2015, Captain California on March 10, 2017 and A Strange Journey into the Unimaginable on his birthday in 2018 all through Strange Music. In between projects, Murs partnered once again with 9th Wonder to create Brighter Daze, which released on December 31, 2015.