Third seed Lleyton Hewitt fell victim to Slovak Lukas Lacko, who stunned the Australian with five breaks of serve to advance into his fifth quarter-final of the season 6-4, 6-2. Hewitt, winner of the Halle title last month, now stands 20-9 on the season.
South African Kevin Anderson ended the run of local pro Donald Young 7-5, 6-3.
The top-seeded world number nine benefitted Thursday from a first-round bye to start his week and took full advantage in a match where he never dropped serve against his number 149 opponent who lost his 15th of the season.
The American claimed the first title of his career in the city at the start of the decade when he won the last edition of the Atlanta tournament in 2001, at age 19, beating Xavier Malisse.
The tournament was dropped after that edition but came back to life for this season after officials bought the sanction of the bankrupt Indianapolis event.
Roddick will face a Friday re-run of that long-ago final in the quarter-final stage at this edition when he plays Malisse.
The seventh-seeded Belgian booked his place by putting out Illya Marchenko of the Ukraine 6-3, 6-3.
"It's a little bit coincidental, given the history here," said Roddick, "We've played plenty since then. There won't be a lot of surprises, we know each other's games well... but it doesn't get any easier."
Roddick has never lost to Malisse in nine career meetings, their last in the Australian Open first round last year. The Belgian took just over two hours to defeat Marchenko, the number 67 with three quarter-final showings this season.
Roddick struck 15 aces against Ram, saved four break points and broke his compatriot on three of four occasions. Only last month, Roddick beat Ram in straight sets in the first round at Wimbledon.
The top seed improved to 33-7 on the season after playing his first match since a fourth-round Wimbledon defeat.
Roddick said that hothouse afternoon conditions made the match a challenge. "This was a hot day, the States in summer is a hot place to play.
"That's what makes tennis tough - it's outdoors in the heat and you are running."
The 27-year-old owns 2010 titles in Brisbane and at his last hardcourt tournament in April in Miami, where he won his 29th career title.