PARIS — Wind was whipping, rain was falling and thick gray clouds overhead were foreboding as Serena Williams double-faulted, then raised her hands in despair and wailed, “I can’t serve!”

As if to prove the point, Williams double-faulted again moments later, before pushing a routine backhand wide to get broken at love.

Truth is, the French Open’s defending champion couldn’t do much properly on this particular afternoon, absorbing the most lopsided loss of her 288-match Grand Slam career. Unable to figure out how to get herself going or counter her unheralded opponent’s aggressive game, Williams was beaten 6-2, 6-2 Wednesday by 35th-ranked Garbine Muguruza of Spain in the second round.

“Nothing really worked,” said Williams, whose older sister Venus also lost. “I don’t know anything that actually worked.”

Ever since last week’s draw, there was talk about a possible all-Williams match in the third round, which would have been their first Grand Slam meeting since the 2009 Wimbledon final. So much for that: Exactly one minute before Serena’s match began, the 29th-seeded Venus’ 2-6, 6-3, 6-4 defeat against 56th-ranked Anna Schmiedlova of Slovakia wrapped up.

“I felt like this was a match that I was most likely going to win,” Venus said. “I don’t know how Serena felt, but I’m sure she feels like that every time she goes on the court.”

Instead of the 25th Williams vs. Williams encounter on tour, it’ll be the 20-year-old Muguruza vs. 19-year-old Schmiedlova.

Serena’s exit came a day after a loss by No. 2 Li Na of China, the first time in the Open era (which began in 1968) that the top two women were gone before the third round at any major tournament.

The biggest beneficiary might be Maria Sharapova, who won the 2012 French Open, lost to Serena in last year’s final and potentially faced a quarterfinal against the American this time. The Russian star beat 42nd-ranked Tsvetana Pironkova of Bulgaria 7-5, 6-2.

Alizé Cornet of France, seeded 20th, was surprised 6-4, 4-6, 6-4 by 18-year-old Taylor Townsend, an American wild-card entry ranked 205th and making her Grand Slam debut.

On the men’s side, No. 15 Mikhail Youzhny of Russia and No. 20 Alexandr Dolgopolov of Ukraine were sent home, while No. 2 Novak Djokovic of Serbia, No. 4 Roger Federer of Switzerland and No. 8 Milos Raonic of Canada won in straight sets.

If an early stumble by seven-time major champion Venus is no longer big news — she’s lost in the first or second round at eight of her past nine Slams — Serena’s departure was shocking for many reasons. She owns 17 major titles, including two in Paris, and was 54-2 on clay over the past three seasons.

Serena remains one major singles trophy shy of Chris Evert and Martina Navratilova, who each won 18.