The 51-year-old replaced Guy Lacombe in 2009 and guided the Breton club to a ninth-placed finish in his first full season in charge.
Consecutive sixth-placed finishes built high expectations for the current campaign but poor recent results have seen the club drift out to 10th place on the back of an eight-game winless run.
Antonetti told staderennais.com: "After four wonderful years, my adventure with Stade Rennais is coming to an end.
"I have decided to leave the club, partly due to the disappointment of this difficult season.
"I will nevertheless remember the many games that allowed us to taste the success that has all too often cruelly escaped us.
"For now, we must not give up and we must give our all out on the pitch to end this season with our heads held high.
"To make my departure official, I could not go without thanking (directors) Francois and Francois-Henri Pinault, Pierre Dreossi and Frederic de Saint-Sernin for the support and confidence they have shown me over the years.
"I wish them, and all the players, fans and members of Stade Rennais, all the best for the future and the success they deserve."
The Corsican coach arrived at Stade de la Route de Lorient after spells with Bastia, St Etienne and Nice.