Roger Federer, who turned 30 earlier this month, on Tuesday cruised past del Potro 6-3, 7-5 for his first win over the Argentine in their last three matches which included the 2009 US Open final. Federer had won their first six meetings, dating back to Wimbledon in 2007.
"I played some tough matches against him in the past and obviously the US Open final sticks out the most," Federer said. "I told him at the net that it was good to see him back."
Federer hammered 12 aces and won 83 per cent of his first-serve points in the 92 minute match on centre court.
Federer said he felt confident but a little nervous going into the second round contest.
"There was a lot of pressure," said Federer, whose only title this season came in Doha in January. "I haven't played much so this was a big match for me.
"I mixed it up well with slices and strong forehands and I was able to retrieve well today."
Del Potro, who upset Federer in five sets in the 2009 US Open final, is climbing back up the rankings after missing much of 2010 with a wrist injury that required surgery.
"We can't compare the 2009 match and this one," del Potro said. "I feel well tonight, but Roger played like No. 1 in the world. He was very confident with his serve."
In the women's tournament French Open champion Li Na also moved smoothly into the third round Tuesday with a straight-set victory over Lucie Safarova.
Li, whose triumph at Roland Garros made her China's first Grand Slam tennis champion, defeated the Czech 6-3, 6-4 to become the first woman to reach the third round.
It was Li's first match win since her second-round exit at Wimbledon, and followed her opening match defeat in Toronto last week.
"I needed some matches for the hard court," said Li, who reached the Australian Open final in January.
"It's always tough, but I was happy I could win the match today," added Li, the fifth seed. "Because I missed a lot, I think I need some matches for me to find the timing on the court."
Fourth-seeded Russian Maria Sharapova, sixth-seeded Wimbledon champion Petra Kvitova and eighth-seeded Marion Bartoli also swept past their opponents in second-round matches on Tuesday.
All of the top eight seeds, led on the women's side by Caroline Wozniacki and on the men's by Novak Djokovic, have first-round byes.
Sharapova routed qualifier Anastasia Rodionova 6-1, 6-3, finishing off the Australian in just 71 minutes.
Sharapova posted just one ace but dominated with her serve winning 57 per cent of her second serves and converting six of seven break point chances.
"I thought I played aggressively and felt better than I did last week, definitely," Sharapova said.
Sharapova will face the winner of a match between Russian Svetlana Kuznetsova and Czech Petra Cetkovska in the next round.
In other first-round matches on Tuesday, in-form former world number one Serena Williams - winner of her last two tournaments - held on to beat tenacious Czech Lucie Hradecka 6-3, 7-6 (7/5).
Unseeded Flavia Pennetta upset 12th-seeded Russian Anastasia Pavlyuchenkova 2-6, 6-3, 6-3, while 13th-seeded Jelena Jankovic of Serbia cruised past Czech Iveta Benesova 6-0, 6-3.
On the men's side, Czech Radek Stepanek - winner of his first title in 2 1/2 years earlier this month when he won the Washington Classic - withstood 21 aces from John Isner to defeat the gargantuan American 7-5, 5-7, 7-6 (7/4).
Jo-Wilfried Tsonga, a Wimbledon semi-finalist and the 15th seed, defeated Croatia's Marin Cilic 6-3, 6-4, while Croatia's Ivan Dodig defeated Latvia's Ernests Gulbis 6-3, 7-6 (7/3) to line up a second-round clash with sixth-seeded Frenchman Gael Monfils.