Kelly was an electronics student while performing part-time in the progressive/psychedelic band Chemical Alice, who released their EPCuriouser and Curiouser in 1981. He was invited to join Marillion when Chemical Alice supported the band, replacing previous keyboardist Brian Jelliman. His first performance with the band was at the Great Northern at Cambridge on 1 December 1981. Kelly has appeared on every Marillion studio album. He also appeared on John Wesley's album Under the Red and White Sky in 1994 and on Jump's album Myth of Independence in 1995 on production and keyboards. He has also played keyboards with Travis for their headlining set at the Isle of Wight Festival (10–12 June 2005), at T in the park in 2005, and at the Live8 set in Edinburgh (6 July 2005). Mark Kelly also played Keyboards for Edison's Children's new album "In The Last Waking Moments..." (featuring fellow Marillion member Pete Trewavas and Eric Blackwood), for the song The "Other" Other Dimension as well as performing vocals with Steve Hogarth and Andy Ditchfield (DeeExpus) on the Edison's Children track The Awakening in 2011. Also in 2011, Mark Kelly performed Keyboards on the epic, King of Number 33 for the prog band DeeExpus
Kelly's work for Marillion has been singled out for praise by Alex S. Garcia, writing for Allmusic. In his review of the band's album Afraid of Sunlight, Garcia claimed: "As usual with Marillion, the keyboards stand out the most."
Kelly is credited with inventing online Crowdfunding to fund the recording of Marillion's 2001 album Anoraknophobia, following on from a fan-funded Marillion tour of the United States in 1997, and pioneered many of the ideas copied by other music artists since. In recognition of this, Kelly was made Co-CEO of the Featured Artists Coalition, an organization which represents the interests of music artists in the digital age. Since 2009, Kelly has also been an elected performer-director of PPL.