The loss snapped Osaka's 16-match winning streak in Grand Slams after she won the 2018 U.S. Open and this year's Australian Open.
The last time Williams was eliminated this quickly at a major came in 2014, when she lost in the second round at Roland Garros then the third round at Wimbledon. The 21-year-old from Japan had been seeking a third consecutive Grand Slam tournament triumph.
Williams sat out four Slams in 2017-18 while on leave to give birth.
Despite her loss here, and despite wins at the most recent US and Australian Opens, this is the first time she was a top seeded player.
"I haven't been on the court as much as I would have wanted to".
Williams has been plagued by injury problems and her long-time coach says that it was likely that she would have lost in the fourth round, even if she had beaten Kenin.
"You can only play who's on the other side of the net", she said.
"I'm definitely feeling super short on matches and just getting in the swing of things", Williams told a news conference minutes after walking off the Philippe Chatrier Court.
One key statistic: Osaka compiled seven break points in the first set but failed to convert a single one.
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It's the end of an up-and-down tournament for Williams, who said she debated daily last week whether to withdraw.
Keys made it to the semifinals in Paris past year.
Like Williams, who dropped eight of the match's first 10 games, Osaka couldn't muster a comeback after falling way behind.
"I felt the chance because her first and second round were tough". "In that first set in particular she hit inches from the line".
"I was not anxious, because losing my serve is happening often", Halep said with a smile.
The mistakes became wilder as the match wore on, Osaka looking resigned to her fate.
Osaka is adapting to the clay but she is a quick study, evidenced by a 7-1 record on the surface this season entering the French Open.
Elsewhere in the women's draw, Halep cruised into the last 16.
"I mean, what the hell?"
She will face world No. 8 Ashleigh Barty on Monday in the fourth round. "It was my best tennis".
US Open and Australian Open champion Osaka had to come from a set down to beat Anna Karolina Schmiedlova and Victoria Azarenka in her opening two matches at Roland Garros. "I can also do what I want". "I think I was overthinking this calendar Slam".