Federer, still aiming to add to his record collection of 17 grand slam singles titles, brushed aside Argentina's Carlos Berlocq 6-3 6-2 6-1.
"For me it was pretty straightforward, to be honest," Federer said. "It's one of those matches I expect myself to win if possible in straight sets and gain confidence in the process."
Nadal made short work of Rogerio Dutra Silva, beating the Brazilian qualifier 6-2 6-1 6-0 in just an hour and 32 minutes and extending his record on hard courts this season to 17-0.
Next up for Nadal is Croatia's Ivan Dodig, who beat the Spaniard the last time they met.
Nadal said: " I have not a good memory of playing against him in Montreal two years ago. It was a very tough match. He's had already two great wins over (Fernando) Verdasco and (Nikolay) Davydenko. He's a dangerous player."
But there were no more late-night heroics from 17-year-old American Victoria Duval, who lost to Daniela Hantuchova 6-2 6-3. The qualifier produced the performance of the day on Tuesday to knock out former champion Sam Stosur but was well beaten by the Slovakian.
Italy's Sara Errani, the women's fourth seed, crashed to a 6-3 6-1 loss to compatriot Flavia Pennetta and made the startling admission that she had choked under pressure.
"I don't know why, but I'm not enjoying going on the courts," she said afterwards. "And that is the worst thing a player can have."
Victoria Azarenka, last year's runner-up, continued her love affair with the New York City hardcourts with a 6-3 6-1 win over Canada's Aleksandra Wozniak.
Men's fourth seed David Ferrer, this year's French Open finalist, beat fellow Spaniard Roberto Bautista 6-3 6-7 6-1 6-2.
Richard Gasquet, Janko Tipsarevic and Dmitry Tursunov all won without dropping a set. The only men's seed to fall was American Sam Querrey, seeded 26th, who lost to Frenchman Adrian Mannarino.
Caroline Wozniacki, Petra Kvitova, Ana Ivanovic and Jelena Jankovic were among the winners in the women's draw, which lost four seeds, the most notable being Errani.
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