The Dane has been No. 1 in the WTA rankings for almost the entire season but never really challenged her Slovak opponent on Court Suzanne Lenglen, having her serve broken five times.
"She played very, very well today, better than me for sure," said Wozniacki, who had never before lost a set to Hantuchova in three previous matches. "She knew what she was going to go out there and do. She was just too good."
Wozniacki's early exit came a day after No. 2 Kim Clijsters was eliminated by 114th-ranked Arantxa Rus, marking the first time that the top two seeded women failed to make the round of 16 at any Grand Slam tournament in the Open era, which began in 1968. It had never happened at the French Open since it began admitting foreign entrants in 1925.
Add that to the absences of the Williams sisters, who are sidelined by health issues, and there is a real lack of star power in Paris now.
"Kim had a tough loss yesterday; I had a tough loss today. That's what happens," said Wozniacki. "Since we're No. 1 and 2, it means that we must be doing something right. It's just unfortunate to lose in a Grand Slam, but that's what happens, and we just need to move forward."
Hantuchova explained the surprises this way: "It just shows how strong women's tennis is at the moment. It's very open."
Wozniacki came into the French Open after winning the clay-court title at the Brussels Open. During the final, she called for a trainer and had her left thigh bandaged.
Although she played the first two rounds at Roland Garros with the same thigh bandaged, she was not wearing any protection on her leg Friday.
Injured or not, the Grand Slam drought remains -- even though Wozniacki said she is not concerned with what others think.
"The only one I feel pressure from is myself to go and give my all for every match and, obviously, I'm a competitor," Wozniacki said. "I love winning. I don't like losing."
Hantuchova beat a current No. 1 player for the first time in her career after six previous losses, including one against Wozniacki this season.
Stosur lost to Gisela Dulko of Argentina 6-4, 1-6, 6-3. The Australian struggled early in dropping the first set but came back and easily won the second. The 51st-ranked Dulko, though, regained control after breaking to take a 4-2 lead in the third and held serve twice to close out the match.
"I was trying to be very aggressive, and I did it very well," Dulko said. "And I think after I have a few ups and downs, and I was lucky to play very good tennis at the end of the match."
The eighth-seeded Stosur, who also reached the semifinals at Roland Garros in 2009, had 35 unforced errors in the match on Court Philippe Chatrier.
"She seemed to be out ahead a little bit better and really kind of be the one dictating the points, which, for me, I'm usually the one able to do that," Stosur said. "Pretty much right from the first game she kind of set that tone, and it was very difficult for me to turn that around."
Dulko equaled her best Grand Slam result by reaching the fourth round. She also won three matches at the 2006 French Open and the 2009 U.S. Open.
Schiavone was broken at the beginning of her match but then won five straight games to take the first set and eventually the match when opponent Peng Shuai of China retired while trailing 6-3, 1-2.
Peng called for a doctor after the first game of the second set and had her blood pressure checked. She looked exhausted in her chair and then started to cry but broke for a 2-0 lead.
Schiavone won the next game before her opponent quit.
"I've been just sick for three or four days," Peng said, adding that she has had a fever. "So it's tough for me to play. I was really tired. I was really sick so my body could not really handle that."
Jankovic, who reached the semifinals at Roland Garros in three of the last four years, broke twice in each set and didn't face a break point.
Mattek-Sands, one of the two remaining American players in the women's draw with Vania King, had 30 unforced errors and received treatment on her right ring finger at 1-1 in the second set.
In other results, No. 13 Svetlana Kuznetsova of Russia, the 2009 French Open champion, advanced by beating Rebecca Marino of Canada 6-0, 6-4, while No. 11 Marion Bartoli of France, a former Wimbledon finalist, defeated No. 17 Julia Goerges of Germany 3-6, 6-2, 6-4.
"Now it's starting to be more complicated matches," Kuznetsova said. "I pass three rounds, so next round going to be hard. Just have to focus and start to play better."
Information from The Associated Press was used in this report.