The world No. 1 Djokovic rolled past Colombia's Santiago Giraldo 6-3, 6-2, 6-1, as the super Serb had to overcome an early service break on Day 4.
"I maybe started a little too defensive because he was hitting the ball very strong," Djokovic said. "But then after, it was the other way around."
The reigning Aussie Open, Wimbledon and U.S. Open titlist has now won 34 of his last 36 Grand Slam matches and is seeking a third straight major title and a third Aussie crown. A title here would put Djokovic in select company, as only four players -- Rod Laver, Pete Sampras, Roger Federer and Rafael Nadal -- have captured three straight Grand Slam championships.
Djokovic will meet big-serving Frenchman Nicolas Mahut in the third round on Saturday at Melbourne Park.
The fourth-seeded Murray, meanwhile, defeated France's Edouard Roger-Vasselin 6-1, 6-4, 6-4 in just under two hours at Hisense Arena.
Murray, who appeared in the last two finals here, including a loss to Djokovic a year ago, is playing his first major event with the legendary Ivan Lendl as his coach.
"It's been good, he's obviously one of the greatest players ever," Murray said. "He's got so much experience and he's a very funny guy. You wouldn't probably expect it by the way he was on the court, similar to myself."
The three-time Grand Slam runner-up Murray will tangle with French left-hander Michael Llodra in his next match.
In the most-anticipated match of the day, the unseeded former No. 1 Hewitt topped a 15th-seeded former top-ranked Roddick 3-6, 6-3, 6-4, as the American retired because of a right hamstring injury.
Roddick summoned the doctor and a trainer after the third set. He fell to the court in the opening set, but played on despite being in obvious pain.
"It's a miserable, terrible thing being out there compromised like that," said Roddick, who is a four-time Aussie semifinalist.
"I wanted to see what I could do. You don't really have much time for clarity in that situation. He's a tough guy to play -- he knew what was going on."
Hewitt said the injury situation was "a nightmare for both of us."
"Obviously he stretched something," Hewitt said. "It's not easy for the person up the other end of the court. It's hard to concentrate when they're having injury timeouts.
"Andy's a great competitor -- he's similar to me. He plays with his heart on his sleeve, has that never-say-die attitude as well. It's never easy to play injured or to pull out of a match. It's not a good feeling."
Hewitt and Roddick have now split 14 career matchups. Hewitt also beat his fellow former U.S. Open champ in the 2005 Aussie semis.
The two-time major champion and '05 Aussie runner-up Hewitt will face rising 23rd-seeded Canadian Milos Raonic here on Saturday. Raonic, who titled in India two weeks ago, downed Germany's Philipp Petzschner 6-4, 5-7, 6-2, 7-5 on Day 4 of this fortnight.
Fifth-seeded David Ferrer, meanwhile, struggled to get past American Ryan Sweeting, who actually held a two-sets-to-one lead before the Spaniard righted the ship en route to a 6-7 (4-7), 6-2, 3-6, 6-2, 6-3 decision. Sweeting recorded nine double faults and piled up 73 unforced errors in the setback.
Up next for Ferrer will be Argentine veteran Juan Ignacio Chela.
Also on Thursday, France's Jo-Wilfred Tsonga, the tournament's sixth seed, defeated Ricardo Mello of Brazil 7-5, 6-4, 6-4 and ninth-seeded Serb Janko Tipsarevic overcame Aussie James Duckworth 3-6, 6-2, 7-6 (7-5), 6-4.
In some action involving a trio of French seeds, Julien Benneteau upset his 12th-seeded countryman Gilles Simon 7-5, 7-6 (10-8), 1-6, 3-6, 6-2, No. 14 Gael Monfils came back to beat capable Brazilian Thomaz Bellucci 2-6, 6-0, 6-4, 6-2, and a No. 17 Gasquet handled Kazakhstan's Andrey Golubev 6-4, 6-2, 3-0, as Golubev retired in the third set.
In other second-round action involving seeds, Kazakhstan's Mikhail Kukushkin outlasted No. 19 Serb Viktor Troicki 5-7, 6-4, 6-2, 4-6, 6-3; Japan's best, No. 24 Kei Nishikori, snuck past Aussie Matthew Ebden 3-6, 1-6, 6-4, 6-1, 6-1; Gil grounded No. 26 Spaniard Marcel Granollers 6-3, 4-6, 6-4, 6-3; a No. 27 Chela eased past Spaniard Pablo Andujar 6-4, 6-4, 6-3; and Llodra outlasted No. 32 Russian Alex Bogomolov Jr. 6-1, 6-3, 4-6, 5-7, 6-4.
One other Thursday result saw Mahut defeat Japan's Tatsuma Ito 1-6, 7-6 (8-6), 6-2, 6-2.
The third round will get underway on Friday, including matches for a pair of all-time greats -- the former world No. 1s Nadal and Federer. The second- seeded Nadal will take on Slovak Lukas Lacko, while the third-seeded Federer will meet massive-serving 6-foot-10 Croat Ivo Karlovic.
Nadal is the reigning French Open champion and owns 10 Grand Slam titles, including an Aussie Open one in 2009 when he beat Federer here in the final. Federer is a record 16-time men's major titlist, including four championships in Melbourne.
Also on Day 5, seventh-seeded former Wimbledon runner-up Tomas Berdych will face 30th-seeded Kevin Anderson, 10th-seeded Nicolas Almagro will battle 21st- seeded Swiss Stan Wawrinka and 11th-seeded former U.S. Open champ Juan Martin del Potro will be opposed by Taipei's Yen-Hsun Lu.
Two other quality matchups will pit 13th-seeded 2011 Aussie Open quarterfinalist Alexandr Dolgopolov against rising Aussie teen and 2011 Wimbledon quarterfinalist Bernard Tomic and 16th-seeded 6-foot-9 American slugger John Isner versus 18th-seeded Feliciano Lopez.