The drubbing was a dismal result for Roddick, whose declining fortunes in recent months have left him fending off questions about retirement.
Djokovic closed out the victory with consecutive aces. Roddick then quickly left the court where he lost three Wimbledon finals, and was noncommittal about the possibility he won't be back.
"It's not close to my mind right now," the 29-year-old Roddick said. "That's not something that I'm going to talk about."
While Roddick was done in only 54 minutes, No. 5-seeded Jo-Wilfried Tsonga of France advanced by winning the longest set in Olympic history. He beat Milos Raonic of Canada 6-3, 3-6, 25-23. The final set lasted three hours and 257 points.
Venus Williams swept two matches in less time. She won the first match on Centre Court in singles and teamed with sister Serena in doubles to win the day's finale on remote Court 12 before an overflow crowd.
Venus earned a second-round victory over Aleksandra Wozniak of Canada, 6-1, 6-3. Later she and her sister advanced to the doubles quarterfinals by beating Angelique Kerber and Sabine Lisicki of Germany, 6-2, 7-5.
"Every day I'm just concentrating on trying to bring my best tennis out," Williams said. "And honestly, if there's a time to do it, it's now."
Williams won her most recent singles title 2 1/2 years ago, and she took a long layoff after being diagnosed in 2011 with an autoimmune disease that causes fatigue. But at 32, she seems rejuvenated by the chance at a record fourth gold medal in Olympic tennis.
"Much improvement in the last few weeks," U.S. coach Mary Joe Fernandez said. "And this is where she feels at home. It's great to be back on the grass."
Williams has won five of her seven major titles at the All England Club, most recently in 2008. Her opponent in singles Wednesday will be the No. 7-seeded Kerber, who beat Timea Babos of Hungary 6-1, 6-1.
Maria Sharapova hit 10 aces under the roof and eliminated Laura Robson of Britain 7-6 (5), 6-3. Sharapova, seeded No. 3, will next play the No. 15-seeded Lisicki, who won when they met in the fourth round at Wimbledon a month ago.
No. 1 Victoria Azarenka of Belarus, playing in tights on a cool, damp evening, drubbed Maria Jose Martinez Sanchez of Spain, 6-2, 6-1.
British hopeful Andy Murray, seeded No. 3, advanced by beating Jarkko Nieminen of Finland 6-2, 6-4. Nieminen won cheers for his scrappy play, including a tumble into the first row in pursuit of a shot.
Also scrappy but more successful was three-time Olympian Lleyton Hewitt, the Wimbledon champion 10 years ago. He beat No. 13 Marin Cilic of Croatia 6-4, 7-5.
Djokovic-Roddick stirred considerable anticipation as second-round matches go, and the crowd was near capacity when they took the court, with both the Serb and the American wearing red, white and blue. For the first time in the tournament, even the Royal Box was almost full.
Roddick started well enough, holding his first two service games, but from there the match quickly slipped away. His big serve was negated as a weapon against the game's best returner, and in baseline rallies Roddick was no match for Djokovic, who deployed his extensive arsenal of slices, drop shots and rocket-like groundstrokes.
Djokovic won seven consecutive games during one stretch, and 12 of the final 13. He finished with 14 aces, lost only 10 points in eight service games and had just six unforced errors.
In the final game Roddick hit a perfect drop shot, but Djokovic ran it down and whipped it crosscourt for a winner. The Serb stood with his arms raised, basking in the roar of the crowd while Roddick shook his head.
"That was one of the best drop shots I ever hit," Roddick shouted to Djokovic when the cheers died down.
Djokovic smiled. Then he hit another ace.
A bronze medallist in 2008 and a Wimbledon champion last year, Djokovic has big hopes in the tournament but plans to savour the Olympics regardless. He enjoys hanging out in the athletes village and met two-time NHL MVP Alex Ovechkin, who agreed to trade a hockey stick for a racket.
"The basics of any Olympic Games is to be alongside the best athletes in the world, to dine with them, to make pictures with them, to chat, exchange experiences," Djokovic said. "This happens only every four years."