Twenty-year-old Kenin may be a new name to many fans but she has had a very good year so far and refused to be overwhelmed by Williams' presence in a 6-2 7-5 victory as Williams' quest for a record-equalling 24th grand slam singles title was put on hold.
Since those early-for-her defeats, Williams had won six of the 14 majors she entered to surpass Steffi Graf's professional-era record of 22 Grand Slam singles championships.
Sixth seed Stefanos Tsitsipas became the first Greek player in 83 years to reach the second week at Roland Garros after he defeated Serbia's Filip Krajinovic 7-5, 6-3, 6-7 (5-7), 7-6 (8-6).
In fact, the 2019 French Open has been about as chaotic as tennis gets.
But she had been living extremely dangerously and against Czech Siniakova, the world doubles No.1 and ranked 42 in singles, she could not find a way back, going down 6-4 6-2.
Her smooth, potent serve started to click and the 10th seed had the fans on Philippe Chatrier court behind her, especially as Kenin contested several line calls.
Keys has had an easy draw to this point but has made a mess of it.
But the young star broke again with another forehand victor to lead 6-5 and took her second match point when Williams hit a backhand long to win in 92 stunning minutes.
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But I've watched Tottenham over the last three or four years under Pochettino and they're a ruthless team as well. Hopefully we're feeling better this time but we know what hard work has to go in to achieve that.
Djokovic looks near-perfect so far at Roland Garros.
Siniakova made her pay, breaking for 5-4 and taking the opener when Osaka sent back her 16th unforced error of the set. The highest women's seeds are now number three Halep, the title holder, and seventh-ranked Sloane Stephens, the 2018 finalists. "I'm still trying to process what just happened", Kenin said, about an hour after the match ended with her covering her face with both hands.
This, as I've said many times, aptly illustrates the fine margins with which tennis matches are won and lost, and moving on to today, we see the remaining fourth round matches take place, from 10am United Kingdom time.
Kenin, the 20-year-old world number 35, will face eighth seed Ashleigh Barty of Australia for a place in the quarter-finals.
Wawrinka, the 2015 champion and a three-time major victor, recorded his 500th match win with a 7-6 (7-5), 7-6 (7-4), 7-6 (10-8) win over Grigor Dimitrov. I had to change my tactics quite a bit throughout the match.
The Romanian showed her best side in a 6-2, 6-1 dismissal of Ukrainian 27th seed Lesia Tsurenko. Siniakova hopes to make a grand slam quarterfinal for the first time in her career.
"It's a lot of emotion", Kenin said in her on-court interview. Vekic actually created more opportunities (nine to eight) and only faced one more service game with break points in it, so the match was arguably considerably more even than the straight-set scoreline.