The R&B soul singer, best known as one-half of Gnarls Barkley, will release the song to trailer his new album The Lady Killer.
The record marks his first studio LP since 2006's Closet Freak: The Best of Cee-Lo Green the Soul Machine, which peaked at number 13 on the UK album chart.
The track was produced by The Smeezingtons, who have previously worked with Sugababes, Travie McCoy and Brandy.
Lyrics to the song include: "I see you driving round town with the girl I love/ And I'm like, f**k you/ I guess the change in my pocket wasn't enough/ I'm like, f**k you."
The music video is expected to premiere next week.
'F**k you' is out in the US on October 4.