The Serb dominated the rest of the match, however, closing it out in 70 minutes to set up a third-round match with Italian Fabio Fognini, who advanced when Tommy Robredo retired with a wrist injury while trailing 7-6 (3), 2-1.
Djokovic said the problem wasn't serious, without elaborating about where specifically he felt the pain.
"It was just an awkward movement," he said. "I was running and I made a quick movement that caused a sharp pain. It's all good now."
Nadal has been nearly invincible this year, dropping only four matches. But he's been vulnerable at this tournament in the past, particularly in the early going he's lost in the third round the last two times he's played.
There was never much of a worry against Dolgopolov, though.
"Is true that sometimes in the end of the season I didn't arrive with the best feelings in my body and the tennis. I lost against players that they decided to play aggressive," Nadal said.
"But generally happy. All the victories are important, and more at the end of the season."
Federer, the fifth seed, had more unforced errors (29) than winners (19) in his first match since a fourth-round loss at the U.S. Open, but he made quick work of the 22nd-ranked Seppi.
"Even though it didn't feel like I've been away for a long time, you kind of know it," Federer said. "Instead of just thinking point for point, what do I want to do, your mind starts to wander not in a bad way, but it's just not that natural yet."
Federer next plays Frenchman Gael Monfils, with a possible quarterfinal with Djokovic looming.
Two other top players, Tomas Berdych and Juan Martin del Potro, also came through with victories despite struggling with injury and illness.
Fourth-seeded Berdych rebounded from a back injury sustained in the semifinals of the China Open last week to defeat Feliciano Lopez 7-6 (5), 6-2. He said after his last match he could barely stand or walk when he retired against Nadal.
"I wouldn't say (my back is) 100 percent, but I decided I was competitive enough to go on court and try to play," he said. "Looks like it was a smart decision."
Del Potro, meanwhile, overcame a fever and 50 winners from big-hitting German Philipp Kohlschreiber to advance 3-6, 6-3, 7-6 (4).
After the match, del Potro said he started feeling sick on Tuesday night and relied on his serve to win the match since running was difficult.
The Argentine withdrew from the doubles to rest for his next match against 11th-seeded Tommy Haas, a 6-4, 6-4 winner over German compatriot Daniel Brands.
Both del Potro and Berdych have a lot to play for this week they're trying to wrap up their spots in the elite ATP Finals in London, a task made slightly easier by the withdrawal on Wednesday of Andy Murray, who is recovering from back surgery.
Del Potro and Berdych would qualify for the eight-man field by making the final in Shanghai.
Federer needs to do a bit more work he's in seventh place in the standings, with a number of players within striking distance.
Three of them moved into the next round on Wednesday: No. 7 seed Jo-Wilfried Tsonga, No. 8 Stanislas Wawrinka and No. 10 Milos Raonic, who is making a late charge by reaching back-to-back finals the last two weeks and capturing one title.
American John Isner, an outside shot for London, however, was ousted by Argentine Carlos Berlocq 6-4, 7-6 (4).