Bidding to win his third straight round match Tuesday at the Australian Open.
Meanwhile, the man he beat in last year's final, Andy Murray, needed to rally from a first-set loss to win his opening match.
The 24-year-old Djokovic lost two of the first three games to Italy's Paolo Lorenzi, then won a whopping 17 in a row to finish off a commanding 6-2, 6-0, 6-0 win at the season's first Grand Slam event.
Meanwhile, a fourth-seeded Murray, who lost in straight sets to Djokovic in last year's Aussie final, needed four sets to down promising American Ryan Harrison, 4-6, 6-3, 6-4, 6-2.
The three-time Grand Slam finalist Murray has been the Melbourne runner-up the last two years. He'll meet Frenchman Edouard Roger-Vasselin on Thursday.
Roddick's second-round opponent will be long-time rival and fellow former No. 1 Lleyton Hewitt.
Battling the heat, Djokovic popped four aces among his 22 winners against Lorenzi, who committed 30 unforced errors and won just 56 percent of his first serves at Melbourne Park.
"It took me, you know, a couple games to get into the right rhythm," Djokovic said. "It's a bit difficult conditions. I think it was really the hottest day since I've arrived here, so I'm trying to get used to that."
Djokovic, of course, began his brilliant 2011 season with a victory at the Australian Open, finishing the year with a 70-6 record. He didn't lose last year until Roger Federer got him in the semifinals at the French Open in June.
Still, Djokovic bounced back to win Wimbledon and the U.S. Open and owns four career Grand Slam titles, including his first Aussie championship back in 2008.
He is trying to become only the fourth player on the men's side to win three or more Australian Open titles in the Open era (since 1968).
"I feel right now -- as I said on the court -- I feel much more complete as a player and as a person as well," said Djokovic, who moved on to face Colombian Santiago Giraldo in the second round.
The powerful Djokovic has won 33 of his last 35 Grand Slam matches, dating back to the 2010 U.S. Open.
"I think it was a learning process for me in the last couple of years. I just have more confidence that I'm playing on right now," Djokovic said. "I just believe that I can win, especially against the biggest rivals in the major events."
Among the other top seeds playing during Tuesday's 32-match slate, No. 5 David Ferrer of Spain was a 6-1, 6-4, 6-2 winner over Portuguese Rui Machado, sixth-seeded Frenchman Jo-Wilfried Tsonga held off Uzbekistan's Denis Istomin 6-4, 3-6, 6-2, 7-5, and No. 9 Janko Tipsarevic of Serbia beat Russian Dmitry Tursunov 5-7, 7-6 (14-12), 6-3, 6-4. Ferrer titled in Auckland last week. Tsonga was a titlist in Doha two weeks ago and the 2008 Aussie Open runner-up to Djokovic. Tipsarevic was a finalist in Chennai two weeks back.
Ferrer's second-round opponent will be American Ryan Sweeting, while Tsonga will meet Brazilian Ricardo Mello.
In other action involving top-20 seeds, No. 12 Gilles Simon of France outlasted Thai Danai Udomchoke 6-1, 3-6, 6-7 (5-7), 6-3, 6-2; No. 14 Gael Monfils of France handled Aussie Marinko Matosevic 7-6 (7-5), 6-3, 6-3; No. 17 Richard Gasquet of France topped quality Italian Andreas Seppi 6-3, 3-6, 6-3, 6-1; and No. 19 Serb Viktor Troicki came all the way back to stop former world No. 1 Juan Carlos Ferrero of Spain 4-6, 6-7 (3-7), 6-2, 7-6 (7-3), 6-2.
Meanwhile, 23rd-seeded Canadian Milos Raonic, who titled in India two weeks ago, drilled Italian Filippo Volandri 6-4, 6-0, 6-2; 24th-seeded Japanese Kei Nishikori defeated France's Stephane Robert 6-1, 7-6 (9-7), 6-0; 26th-seeded Spaniard Marcel Granollers snuck past American Jesse Levine 6-0, 7-6 (7-4), 5-7, 5-7, 6-3; 27th-seeded Argentine Juan Ignacio Chela dismissed American journeyman Michael Russell 7-6 (7-3), 6-3, 6-4; and 32nd-seeded Russian Alex Bogomolov Jr. whipped Spaniard Daniel Gimeno-Traver 6-3, 6-2, 6-4.
The aforementioned Aussie hero Hewitt advanced with a 7-5, 6-4, 3-6, 7-5 Day-2 victory over German Cedrik-Marcel Stebe. The two-time Grand Slam champion was the Australian Open runner-up back in 2005.
Hewitt will meet Roddick for a 14th time on the ATP World Tour, with the American holding a slight 7-6 lifetime advantage. Hewitt beat Roddick in the '05 Aussie semis.
Several other men reached the round of 64, including Sweeting, Frenchmen Michael Llodra and Julien Benneteau, and German Philipp Petzschner. Sweeting topped German Matthias Bachinger 6-4, 6-4, 6-2. Benneteau was a runner-up in Sydney last week.
The second-seeded French Open champion Nadal, who captured the 2009 Aussie Open crown and owns 10 major titles, will face former world No. 2 and oft- injured German Tommy Haas, while the 16-time major titlist Federer, who owns no less than four Aussie Open championships, will battle German Andreas Beck.
Also on the Day-3 schedule will be seventh-seeded Czech Tomas Berdych, 10th- seeded Spaniard Nicolas Almagro, 16th-seeded 6-foot-9 American John Isner and former Aussie Open runner-up Marcos Baghdatis, who will be opposed by 21st-seeded Swiss slugger Stan Wawrinka. Isner should have his hands full with former top-five star and former Wimbledon runner-up David Nalbandian.