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Williams has been sidelined since July with an injury she picked up after cutting her foot on broken glass in a Munich restaurant, shortly after winning her fourth singles title at Wimbledon.
“I am likely out for the year now,” Williams announced Sunday on her official website www.serenawilliams.com.
Williams said she was hoping to get back sooner and was back training but had re-injured the foot in practice.
“In order not to make this worse, I have to chill on my physical workouts but I will immediately begin rehabbing as soon as I get the Doc’s OK. Keep me in your prayers (I need them),” she wrote.
If Williams is sidelined for the remainder of the season, it would be a huge blow to the WTA Championships later this month, as well as for the United States when it plays Italy in the Fed Cup final next month in San Diego.
Venus Williams had already announced she would miss the rest of the season with a left knee injury.
The two sisters had originally hoped to play for the US team in the Fed Cup tournament.
Serena had already this weekend announced she was pulling out of a tournament in Austria.
A comeback at the modest, 220,000 dollar Linz tournament would have allowed Williams to get herself in condition for the Masters in Doha at the end of October, which is played on the same surface.
Serena Williams will lose her world number one spot when the latest WTA rankings are published on Monday, after Danish 20-year-old Caroline Wozniacki secured top spot by reaching the quarter-finals at the Beijing tournament.
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