The 35-year-old has been struggling with a back injury that kept him out of France's Six Nations squad earlier this year, and he has decided that now is the time to end his 13-year career.
"I'm officially stopping playing rugby," De Villiers said on the Stade Francais website, www.stade.fr.
"It's something that I have thought hard about, and for me it's the right decision.
"Since the back injury, which I have had since the end of December, I tried to come back but I don't want to play just for the sake of playing."
The South African-born De Villiers won 69 caps for France and won five Top 14 championships with Stade.