The seven-time champion had to come from behind for the second match in a row to beat Martin Klizan 4-6, 6-3, 6-3, 6-3.
Nadal criticized tournament organizers for scheduling his match with Klizan late on Thursday with rain predicted. The forecast proved correct, and the match was postponed a day, while Nadal's next opponent Fabio Fagnini won earlier Thursday and will have a day's rest before their match Saturday.
"That's not fair," Nadal said. "Today I was playing almost three hours on court, and my (next) opponent was watching the TV in the locker room."
Because the second-round match against Klizan was postponed a day, Nadal must win six matches in the final 10 days of the tournament to reclaim the trophy.
While Nadal's behind schedule and unhappy about it, Roger Federer and Serena Williams easily moved into the fourth round. Defending champion Maria Sharapova won a rain-interrupted match to reach the third round.
Entering the tournament, Nadal had lost only 14 sets in 53 matches at the French Open. Now he has dropped the opening set in each of the first two rounds.
When Klizan's final shot sailed out, Nadal gave the cheering crowd a relieved thumbs-up and managed a weak smile. The Spaniard blamed his patchy play on a lack of practice time because of rain.
"That makes the things not easy," Nadal said. "So I started the match probably with not the right intensity, with more doubts than usual. The positive thing was that I had a good reaction at the beginning of the second set. Even if I didn't play fantastic, I played the way that I had to play, with intensity, you know, with passion."
Nadal also lost the first set of his opening match against Daniel Brands and was down 3-0 in the second-set tiebreaker before he rallied. Last year lost one set in the entire tournament en route to a record seventh Roland Garros title.
Federer, seeded No. 2, was broken in the opening game but held the rest of the way and eased into the fourth round by beating No. 30 Julien Benneteau of France, 6-3, 6-4, 7-5.
Federer hit 31 winners with 21 unforced errors to eliminate Benneteau, who had won when they played at Rotterdam in February.
"I'm able to play quite aggressive at the moment," Federer said. "I don't know if I can keep that up. But the important thing is to keep the errors somewhat low because otherwise it's just silly aggressiveness. It has to be controlled aggression."
Federer seeks a record 18th Grand Slam title, and his first since Wimbledon last year.
No. 12 Tommy Haas became the first 35-year-old since 2007 to reach the French Open's third round, beating 20-year-old American qualifier Jack Sock 7-6 (3), 6-2, 7-5.
Haas next plays No. 19 John Isner, who overcame a two-set deficit for the first time to win an all-American match against Ryan Harrison, 5-7, 6-7 (7), 6-3, 6-1, 8-6.
Isner is the last U.S. man in the field, because No. 18 Sam Querrey let a lead slip away in a 2-6, 6-3, 2-6, 7-6 (2), 6-2 loss to No. 15 Gilles Simon of France in the third round. Simon faces Federer next.
An American player left the women's tournament when No. 29 Varvara Lepchenko was eliminated by No. 8 Angelique Kerber of Germany 6-4, 6-7 (3), 6-4.
The No. 1-ranked Williams, seeking her first French Open title since 2002, beat Sorana Cirstea 6-0, 6-2 and has lost only six games in three matches. Williams swung hard, as always, but committed only 16 unforced errors and extended her career-best winning streak to 27 matches.
"I play very aggressive," she said. "That's important for me, because I want to keep on winning here."
Sharapova needed only 15 minutes to close out a 6-2, 6-4 victory over 19-year-old Eugenie Bouchard. The match was suspended on Thursday night with Sharapova up a break in the second set at 4-2, and she was relieved to finish.
"It was such a long day yesterday, and obviously it's always difficult to have to come back," Sharapova said.
With a morning start on another chilly, damp day in Paris, fans were late arriving at Court Suzanne Lenglen, which may have contributed to Nadal's malaise. The match was his first against the No. 35-ranked Klizan, and the slender Slovak's aggressive left-handed strokes from the baseline quickly made an impression.
"Wow," Nadal exclaimed after one winner by Klizan whizzed past.
Nadal's shots lacked their usual depth and sting at the outset, and he pushed a forehand wide at the end of a long rally to lose serve for the first time.
Klizan served out the set before Nadal gained a foothold, racing to a 4-0 lead in the second set.
Nadal swept the final eight points of the third set to take command. His groundstrokes started landing beyond the service line more consistently, and dogged defense helped bail him out.
He said his annoyance about the scheduling won't linger.
"When something like that happens, all we can do is just accept it, try to be positive," he said. "Now is not the time to be angry or to have negative thoughts."
Now 54-1 at the French Open, Nadal seeks to become first man to win eight titles at the same Grand Slam event.