Djokovic, a runner-up in 2007, beat Australia's Carsten Ball 6-3, 6-4, 6-4 while Roddick cruised past France's Marc Gicquel 6-1, 6-4, 6-4.
Both will face American opponents in round three: Serbia's Djokovic against No 276-ranked Jesse Witten and Roddick against big-serving compatriot Jon Isner.
There's a lot more against John that's out of my hands,” Roddick said.
“I know he's going to come out and just play super, super aggressive,” Roddick said. “I'm just going to have to stay the course.”
It was a good day for the seeded men, who all progressed, including No 8 Nikolay Davyenko and No 10 Fernando Verdasco, who both won in straight sets.
Verdasco has a difficult task in the third round against German Tommy Haas, who also was a straight-sets winner Thursday, while Davydenko will face Swiss Marco Chiudinelli.
It was much less predictable in the women's draw, where Elena Dementieva and Jelena Jankovic were high-profile casualties.
Dementieva, the No 4-seeded Russian was beaten by teenager Melanie Oudin 5-7, 6-4, 6-3 to thrill the American fans, while Jankovic _ grieving over the death of a grandmother _ was edged out 6-3, 6-7 (4), 7-6 (6) by Kazakhstan's Yaroslava Shvedova. The 17-year-old Oudin added Dementieva scalp to her win over former No 1 Jankovic at Wimbledon.
“She was in the court, not afraid to play, playing very aggressively, really enjoying this atmosphere and the crowd support,” Dementieva said.
“It looks like she has a good future.” Oudin's next chance for a high-profile upset will be against another former top-ranked player Maria Sharapova.
The Russian, seeded 29th as she climbs in the rankings following a long injury layoff, downed American Christina McHale 6-2, 6-1.
Dinara Safina was again less than authoritative, but the top seed won through to the third round, beating Germany's Kristina Barrois 6-7 (5), 6-2, 6-3. Her next opponent will be Czech Petra Kvitova. Former champion Svetlana Kuznetsova, No 9 Caroline Wozniacki and Safina are the only top-10 seeded players left in the top half of the draw. That opened the door for Sharapova to make a charge to the quarters, where she was on course to face Kuznetsov.