The track, by covered by Celtic Woman singer Mairead Carlin and Glee star Damian McGinty, is being released in a joint venture between Walled City Records and Carly Simon's record company Iris Records.
The video for the song will feature many of the highlights of the City of Culture year including Lumiere, Radio One's Big Weekend, the Fleadh, the Walled City Tattoo, The Return of Colmcille and Other Voices.
Let The River Run was performed by Carlin and McGinty at the opening Sons and Daughters concert at The Venue in January last year.
Legendary singer-songwriter Carly Simon said she was "moved to tears" on first hearing the new version of her iconic song.
"I just played it and cried my eyes out and I'm still crying," she said.
"It's absolutely stunningly wonderful. Thank you for doing me proud."
The singer invited Carlin and McGinty to perform the song with her at a gala event in Beverly Hills, California earlier this month.
They have made the song famous in Derry and it has now become a theme song for Derry, and I thank them so much for that.
The star-studded event included guest speakers Former Secretary of State Hillary Clinton and HBO CEO Richard Plepler, as well as celebrity attendees Ted Danson and wife Mary Steenburgen, Diane Lane, Jane Fonda, Harvey Weinstein and Ed Begley Jr.
McGinty described the performance as a "very proud moment" in representing Derry~Londonderry on a worldwide scale.
Carlin added: "Singing Let The River Run with Carly is something I will never forget."
Frank Gallagher, who produced the track, said: "We were delighted when Carly Simon reacted so positively to our version of her great song.
"Let The River Run has become synonymous with the success of the City of Culture year and it is very fitting that a year after it was first heard, it is to be released as a single at the start of 2014."
The single is available for pre-order now and available for download at midnight 20 January.