Wawrinka, 30, ranked ninth best men’s player in the world, previously separated from her briefly in 2011 before getting back together.
The couple was married in December 2009 in Lausanne, Wawrinka’s home town.
The former Ilham Vuilloud was previously a fashion model and a presenter with TSR, the French-language state broadcaster.
The couple have a daughter, Alexia, who is now five.
"We have enjoyed ten fulfilling years, with all the ups and downs that every couple experiences, but sometimes life is more challenging than one would hope”, Wawrinka said in a statement in English on his Facebook page.
“Ilham and I were both blessed to create a family when our wonderful daughter Alexia was born in 2010, “ he said.
“We have always tried to live our lives as a team and as a family, despite the challenges we have faced due to the demands of my career,” Wawrinka said.
“To my great regret this isn’t possible anymore.”
The 2014 Australian Open champ has been struggling on the court recently after getting knocked out of the Grand Slam tournament Down Under in the semifinals in January.
Last week, defending the Monte Carlo Masters, he lost in the third round, following a string of other disappointing showings.
When he separated from his wife before, Swiss media reported her saying it was because he wanted to dedicate himself to his tennis.
In January 2014 he ranked third in the world but now he faces getting booted out of the top ten.
"Ilham will always be the mother of my daughter and a person that I have a lot of love and respect for,” Wawrinka said. “We will always remain as a family, “ he said.
“Now my priority is to do everything to protect Alexia during these challenging times."
Wawrinka added that he did not wish to comment further on the breakup.
“I hope that the fans and the media will understand that I’ve always been very protective of my private life and wish to continue to do so not giving any further information about the situation."