"I'm really just dead. I need some weeks off where I don't think about tennis and kind of regroup," Williams said after the match. "I've had a long couple of years, and I'm really a little fatigued."
Williams, the top seed and defending champion in Charleston, was looking for her second straight title and her third this year after winning a record seventh Sony Open last weekend.
But with only 18 minutes gone in the match, she was down 0-5 on the green clay at the Family Circle Tennis Center. Williams rallied, winning four straight games surrendering only six points and it looked like Cepelova's lead would be short-lived. But the 20-year-old Cepelova came back and, holding serve in the final game, was able to win the set.
Williams said later she feels emotionally and physically spent.
"Definitely a little bit of both. But again, I think Jana played really well for her today," she said. "The good thing is I know I can play a lot better. So it's always really positive for me."
Cepelova's run out to a quick lead silenced the crowd, which was in the defending champion's corner
"I have 5-0 and I was a little bit nervous, but I did it," said Cepelova, ranked 78th in world. "You know, you play against No. 1 player and you never know. It was a tough situation for me, but I'm really happy that I keep the set."
Williams' sister, Venus, also struggled on Tuesday, but edged Barbora Zahlavova Strycova 6-3, 0-6, 7-5.
"I've actually been pretty sick lately -- I've been having like a bug," Venus Williams she said after the match that lasted 2 hours, 15 minutes. "You just have to play your way into the week and just continue to feel better."
Venus Williams, a seven-time Grand Slam champion has battled injuries and Sjogren's syndrome, a fatigue-causing autoimmune disease, during the past two years.
"I haven't gotten rid of it. I wish I could have. Unfortunately it just clings to me," Williams said. "I've just learned to handle it mentally and also I try to do things all the time, just always going for optimal health."
Williams seemed in control of the match after she won the first set, surrendering only two points in her last two service games.
But the 56th-ranked Zahlavova Strycova rattled off seven straight games to shut out the 28th-ranked Williams in the second set and go up 1-0 in the third.
Williams rallied for a 5-4 lead in the third set, but Zahlavova Strycova fought off four match points to tie it at 5-all. Williams then earned a break in the next game -- helped by a final point double-fault -- and held at love to win the match.
Williams staved off what could have been her earliest exit at the Family Circle. She's making her seventh appearance at the tournament she won a decade ago. Williams, who won the Dubai title this year, said she didn't get down on herself after dropping the second set.
"My gosh, if you are careful and you don't play almost perfectly, every single player is so talented out here that you can drop a set or the match," Williams said. "So it's stay focused, really believing in yourself and taking some chances and making your shots."
American Vania King beat Julia Glushko 4-6, 7-5, 6-3, and Daniela Hantuchova of Slovakia defeated American wild card Shelby Rogers 7-5, 7-5. No. 13 Elena Vesnina of Russia cruised past Anna Schmiedlova of Slovakia, 6-2, 6-1, and Shuai Zhang of China outlasted Su-Wei Hsieh of Taiwan 3-6, 7-6 (5), 7-6 (0).
In other matches, No. 14 seed Andrea Petkovic of Germany eliminated Lesia Tsurenko of the Ukraine, 6-7 (2), 6-4, 6-1, and Spain's Lourdes Dominguez Lino defeated countrywoman Anabel Medina Garrigues 6-3, 6-2. Peng Shuai of China defeated Caroline Garcia of France 6-2, 6-3.
Eugenie Bouchard of Canada, seeded No. 6, dispatched qualifier Alla Kudryavtseva of Russia, 6-2, 6-0 while No. 7 seed Samantha Stosur of Australia eliminated Yaroslava Shvedova of Kazakhstan 6-3, 5-7, 6-1. Teliana Pereira of Brazil ousted eighth-seeded Sorana Cirstea of Romania 3-6, 6-3, 7-6 (0). Marina Erakovic of New Zealand defeated Nadia Petrova of Russia, who received a wild card for the tournament, 4-6, 6-3, 6-4.