Defending French Open champion Jelena Ostapenko lost her opening match to Ukraine's Kateryna Kozlova at the season's second major.
Williams, 37, who is due to compete in the doubles with sister Serena in Paris, went out when she sent a forehand into the net.
Something even more unusual happened at Roland Garros, too: Venus Williams was beaten in her opening match at a second consecutive major, the only time in her lengthy, distinguished career she's had such early back-to-back exits.
In 2017, ranked only 47th and 20 years old, Ostapenko became the first woman since 1979 to win her initial tour-level trophy at a Grand Slam tournament.
Kozlova, who is No. 67 in the WTA rankings, earned her first victory against anyone ranked in the Top 30. Moments later, Ostapenko was gone, swiftly heading to the locker room. Ostapenko raised her left hand to acknowledge the crowd's applause, but she kept her eyes focused on the ground as she walked off.
Elsewhere, Britain's Kyle Edmund will be targeting a run deep into the second week, while 2016 champion Novak Djokovic will hope past glories can inspire him to the latter stages at Roland Garros.
Milwaukee Bucks' Sterling Brown says he felt 'defenseless' during arrest
Scott Walker says he believes video of Milwaukee police using a stun gun on a Bucks player shows why body cameras are important. He said that before moving to Milwaukee his interactions with police had been for minor things, like traffic tickets.
Roman Abramovich ‘eligible to become Israeli citizen’
The move could pay off financially as new Israeli citizens are exempt from paying tax on foreign income for 10 years. His British visa expired last month and sources have told Reuters it was taking longer than usual to get it renewed.
Faf, Ngidi taste IPL victory with CSK
Watson failed to open his account in the first 10 balls of the innings, but there was no looking back once he got into the groove. A lot of people talk about stats, so tonight is 27th, my jersey number is seven and this is the seventh final for us.
Kozlova stayed steady despite the enormity of the moment and while dealing with a blister on the back of her right foot.
"And then you go to the match and try to be positive, but everything goes not your way, and you still try to be positive, but then you lose the match and of course you can not be positive anymore".
She only returned to the court earlier this week in Nuremberg, and also needed medical attention after struggling with blisters on Sunday.
"I was warming up and my coach said, "hey look" and we saw up on the board that I was playing a different opponent", said 27-year-old Dimitrov, a former Wimbledon semi-finalist, after his 6-1, 6-4, 7-6 (7/1) win.
On this day, she was not.
It was confirmed just before 7pm that play would not be restarted tonight.