Rennes are 10th in Ligue 1, after reaching as high as fourth in January, and have little to play for in their remaining six league games.
An eight-match winless streak dashed any hopes of playing in European competition next season.
"After four nice years, my adventure with Stade Rennes will end. I have decided to leave the club, partly because of this difficult season ending," Antonetti was quoted as saying on the club's website.
The club made it clear that Antonetti's departure would be effective at the end of the season.
Under Antonetti, Rennes reached sixth place in Ligue 1 in 2011 and 2012. The club have not said who would replace the 51-year-old as coach.
- Sports & Recreation
- Stade Rennes