Niland, the qualifier from Ireland, ranked 197th in the world, wasn't expected to pose much problem for Djokovic, who has surged to the top of the world rankings with nine titles this season -- including two Grand Slams.
But a bout of food poisoning that lingered from Sunday morning had left the 29-year-old Niland physically weakened, and Djokovic needed just 44 minutes to take a 6-0, 5-1 lead before Niland called it a day.
"I felt great on the court, and that's something that's really important for the start of the tournament," Djokovic said of his abbreviated appearance on the Arthur Ashe stadium.
The quick match may prove a boon for Djokovic, who suffered just his second defeat of the season when he retired from the Cincinnati final against Andy Murray this month with a sore shoulder.
"I don't think I'm lacking any time on the court or matches," said Djokovic, who has now won 58 of his 60 matches this year and lifted nine titles. "This year has been a very long year. So I really don't mind that I spend less time on the court.
"It's unfortunate for my opponent, obviously. He had food poisoning he told me after the match."
"There are always things that could have been done better, but I think I had a pretty solid start," said Azarenka, who drew the short straw among the top women's seeds when she was put on a path to a possible third-round clash with Williams.
Williams is seeded just 28 here, after a rankings slide due to her nearly year-long absence with a series of health problems. Williams has nevertheless stamped herself a favorite with two hardcourt victories in the build-up to the Open, and her potential third-round clash with Azarenka was the talk of the draw last week.
Azarenka insisted she wasn't worrying about Williams just yet.
"I'm not interested about that before I go out there," she said. "We'll talk about it later maybe."
In other early matches, Spanish fifth seed David Ferrer rallied to reach the second round with a 2-6, 6-3, 6-0, 6-4 victory over Russian Igor Andreev.
French 11th seed Jo-Wilfried Tsonga, who missed the US Open last year with a knee injury, returned with a 6-4, 6-4, 6-4 victory over Taiwan's Lu Yen-Hsun.
Wimbledon semi-finalist Sabine Lisicki of Germany romped to a 6-3, 6-3 victory over Alona Bondarenko in just 70 minutes.
Lisicki, who arrived in New York fresh from a WTA triumph in Dallas on Saturday, booked a second-round clash with two-time US Open champion Venus Williams.