Giving away 14 years to the swashbuckling young Greek on a baking afternoon, 2015 champion Wawrinka prevailed in a riveting five-hour battle of the backhands in front of an enthralled Court Suzanne Lenglen crowd.
Tsitsipas, 20, looked on the brink of victory at 5-5 in the fifth set but could not convert any of the three break points that came his way and 28th seed Wawrinka went on to claim a 7-6(6) 5-7 6-4 3-6 8-6 victory.
Tsitsipas ended up coated in clay dust after several diving volleys and the drama went right down to the last point when Wawrinka’s sliced backhand pass just touched the sideline — leaving Tsitsipas crestfallen.
"I think today was really special, and the match was amazing, five hours' match, five sets," three-time Grand Slam champion Wawrinka said after the classic. The crowd stayed all the match.
"This kind of atmosphere, for sure, I enjoyed. I enjoy a lot. That's the reason why I still play tennis, and that's the reason why I'm practising every day to try to win big matches like that.
"So for sure, when I'm on the court I try to enjoy and remember also everything I have done to be here."
Sixth seed Tsitsipas admitted defeat, when he was playing such scintillating tennis, had left him in tears.
"It's been a long time since I cried after a match, so emotionally it wasn't easy to handle," a devastated Tsitsipas reflected. "I will try to learn from it as much as I can.
"I feel exhausted. I never experienced something like this in my life. I feel very disappointed at the end.
"My mind is so empty right now. I cannot even think. I was so close, so close. I give him room to do whatever he liked on all those break points. So many break points. So many. I didn't play them. I was expecting someone else to play them for me. I didn't play them.
"It's the worst feeling ever. Especially when you lose. You don't want to be in my place."
