The Pulp frontman will step down from Jarvis Cocker's Sunday Service at the end of December.
The show launched in January 2010 and has been a weekly show on the network ever since, although Cocker has taken occasional breaks to pursue his other creative projects.
Stars including Russell Crowe, Cillian Murphy and Sam Taylor-Johnson have all filled in for him recently.
Cocker has been absent from the show since July but will return for five more shows, with the last to be broadcast on Sunday December 31.
The singer said: "It's not goodbye, it's just farewell. We wanted to say farewell properly and so we're going to do a run of five extra-special shows throughout December, starting this Sunday. Let's keep warm together."
Paul Rodgers, head of 6 Music, said: "Jarvis has been integral to 6 Music and its development, so we are very sad to see him leaving the Sunday Service and I'd like to thank him for an inspirational show.
"It's been a real mould-breaker and I don't think anything like it exists elsewhere in broadcasting.
"Jarvis will always be an important part of the 6 Music family and we are looking forward to him returning to work on new projects with us."
From January 7 the slot will be filled by Amy Lame for a new show.
She said: "I'm so pleased to be the latest addition to the 6 Music family. I've been a dedicated listener since the inception of 6 Music, and to now have a weekly show on the station I love so much is a dream come true.
"Jarvis has always been an important part of my Sundays and I - like many others - will miss him.
"I can't wait to get cracking, connect with listeners, and keep the alternative spirit of music and culture alive and well."