Outplayed from start to finish, Williams lost 6-2, 7-5 to the 35th-ranked Kenin, ending her latest bid for a 24th Grand Slam title with her earliest loss at a major tournament in five years.
Williams, who suffered her earliest Grand Slam exit since Wimbledon 2014, was given a standing ovation as she walked off Court Philippe Chatrier while sections of the crowd jeered her conqueror.
"It's a lot of emotions", said Kenin, who saw her father and longtime coach in the stands filming her on-court interview with a smartphone.
But Osaka said Saturday that she felt exhausted and was dealing with a headache. She went on to reach the finals of Wimbledon and the US Open before wasting match points during a quarterfinal loss at the Australian Open.
"I was pretty far away - I have not been able to be on the court as much as I would have liked to".
"I think this tournament I have had a feeling that was different to the other grand slams, or every other grand slam that I have played, because usually I find it very freeing and fun, and this time around I was kind of tense the entire time", Osaka told reporters.
"You know, it's weird, but I think me losing is probably the best thing that could have happened".
She'd never shared a court with Williams before, although Kenin did try to set up a practice session during the offseason by texting Mouratoglou.
Keys, a semifinalist in Paris a year ago, advanced by beating qualifier Anna Blinkova 6-3, 6-7 (5), 6-4.
Kenin wasn't even born when Williams made her Paris debut in 1998.
After Williams showed fight by going from 3-1 down to 4-3 ahead in the second set, Kenin hung in there. She lost 6-4, 6-2 in 77 minutes.
When the family initially lived in New York Alex worked as a computer programmer and Svetlana as a nurse. Having played the real Serena Williams, she posed for a picture with a poster of the champion, dreaming of the day when she might join her on that wall. That potential was confirmed when Kenin won the U.S. Tennis Association's girls 18s championship, and she recently has been tested in pressure situations on the American Fed Cup team.