Roared on by the energetic New York crowds, Nadal and Williams both turned on a masterclass of power hitting at Arthur Ashe Stadium.
Nadal, who missed last year's U.S. Open because of a chronic knee problem, showed his intentions to make up for lost time as he demolished American wildcard Ryan Harrison 6-4 6-2 6-2.
Bouncing around the unforgiving Flushing Meadows hardcourt like a kangaroo, the Spaniard chalked up 28 winners despite the blustery conditions at the U.S. National Tennis Center.
"For me, the chance to be back here playing is great," said Nadal. "The first match after two years in the Arthur Ashe is a great feeling."
Always a showstopper, Williams made a dramatic entrance to the centre court, arriving with her hair braided and dyed a deep purple.
Her fingernails were also polished in the same vivid fuschia and she showed no signs of the back problems that have sidelined her for most of the year as she dispatched Belgium's Kirsten Flipkens 6-1 6-2.
The 33-year-old American, the second oldest player in the women's singles draw, provided a glimpse of the form that saw her win the U.S. Open in 2000 and 2001 as she romped to victory in just one hour and 24 minutes.
"It's good to be back," she said.
Williams has only played 18 matches this year and slipped to 60th place in the world rankings while Flipkens is enjoying the best season of her career.
The 27-year-old made the semi-finals at Wimbledon in July, her best result at any grand slam, and was seeded 12th for the U.S. Open. Earlier this month, she beat Williams in Toronto after losing the first set 6-0.
"I was glad to close it out today," said Williams, whose younger sister Serena was scheduled to play her opening match on the centre court later on Monday.
EARLY UPSET
Flipkens was the first notable casualty in a wide open women's draw that promises to be one of the most competitive years.
China's Li Na, the 2011 French Open champion and runner-up in Australia this year, needed just 64 minutes to crush Olga Govortsova of Belarus 6-2 6-2.
And Poland's Agnieszka Radwanska, the third seed, was even more ruthless, thumping Spain's Silvia Soler-Espinosa 6-1 6-2 in 63 minutes in the opening match on the centre court.
There was an early upset in the men's draw when Japan's Kei Nishikori, Asia's highest-ranked man, was beaten by British qualifier Dan Evans.
The Englishman, ranked 179th, stormed to a 6-4 6-4 6-2 win over the 11th seed to set up a second round meeting with combative Australian Bernard Tomic, who won a five-set slugfest with Spain's Albert Ramos.
"It's definitely a good one," said Evans, playing in his first U.S. Open. "That was pretty good out there to play so well and against someone so highly ranked."
Just as the first matches were starting, American James Blake announced he was retiring after the August 26-September 9 championships, ending a 14-year career where he rose to number four in the world rankings.
One of the most respected players on the circuit, Blake was inspired to take up tennis after hearing Arthur Ashe address a group of young players at a tennis clinic in Harlem.
He turned professional in 1999 after attending Harvard University and despite enduring moments of hardship, including breaking his neck in a freak accident in Rome in 2004, he retained a sense of perspective.
"This is my last tournament," he said. "I have had 14 pretty darn good years on tour, loved every minute of it, and I definitely couldn't have asked for a better career."
(Editing by Frank Pingue)
