Roared on by the energetic Flushing Meadows crowds, the trio turned on a masterclass of power hitting at Arthur Ashe Stadium before New York's fickle weather brought proceedings to an early end.
A late rain shower forced tournament organisers to abandon the opening day's play before former world number one Roger Federer was about start his match against Slovenia's Grega Zemlja.
Nadal, who missed last year's US Open because of a chronic knee problem, demonstrated his intentions to make up for lost time as he demolished American wildcard Ryan Harrison 6-4 6-2 6-2 during the day session.
Bouncing around the unforgiving hardcourt like a kangaroo, the Spaniard chalked up 28 winners despite the blustery conditions at the US 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."
Serena needed just one hour to remind everyone why she remains the overwhelming favourite to win the women's title as she demolished Italy's Francesca Schiavone 6-0 6-1.
The American showed no mercy against her opponent, who won the French Open in 2010 and was a finalist in Paris the following year, conceding just 23 points in the 60-minute romp.
"I knew playing a former Grand Slam champion in the first round was a really tough draw so I decided to be super serious," she said.
Not to be outdone, her older sister Venus rolled back the years with a headturning appearance on the centre court, arriving with her hair braided and dyed a deep purple.
Her fingernails were also polished in the same vivid fuschia and no repeat of the injury 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, the second oldest player in the women's singles draw, provided a glimpse of the form that saw her win the US Open in 2000 and 2001 as she strolled to a surprisingly quick win.
"It's good to be back," said Williams, who has only played 18 matches this year and slipped to 60th 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 US Open but found Williams too hot.
"When Venus is on fire, she is on fire," said Flipkens.
"If Venus is fit and she's focused she's a top 10 player. Today she was like a top 10 player."
Flipkens was the first notable casualty on a day where most of the top players safely made it through.
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 center court.
There was an early upset in the men's draw when Japan's Kei Nishikori, Asia's highest-ranked man, was beaten 6-4 6-2 6-2 by English qualifier Dan Evans, ranked 179th.
"It's definitely a good one," said Evans, playing in his first US Open. "That was pretty good out there to play so well and against someone so highly ranked."
Russia's Alisa Kleybanova made an emotional return to the Grand Slam circuit, more than two and a half years after she was diagnosed with Hodgkin's lymphoma, a form of blood cancer.
The now 24-year-old underwent chemotherapy through most of 2011 and after beating the disease she decided on a comeback.
"All those things are over for me now," she said after defeating Puerto Rico's Monica Puig 6-4 3-6 7-5 .
"I went through them. I came out as a winner in that battle."
Just as the first matches were starting, American James Blake announced he was retiring after the 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."
- Sports & Recreation
- Arthur Ashe
- Kirsten Flipkens