The fourth-seeded Russian was at his powerful best as he outclassed the 17-year-old Djokovic, storming to victory in just 74 minutes under the lights in Rod Laver Arena.
Safin, beaten by Roger Federer in the final last year and by Thomas Johansson in 2002, looked sharp from the start and his big-hitting all-round game proved too much for the world number 188.
"Two times in the final, it's too disappointing to think about," Safin said. "But hopefully I'll have a chance to be in the final a third time and hopefully this year."
Twelve months ago, Safin beat Andy Roddick and Andre Agassi in two epic five-set battles on his way to the final, only to run out of steam as Federer swept him aside in straight sets.
"I am trying to spend as little time on the court as possible as you never know when you are going to have to end up playing more," he said.
"Basically it's better to be fresh."
Djokovic showed signs of potential and Safin said he had not taken anything for granted despite a gap of 184 places between them in the world rankings.
"You have to be really careful with these upcoming young players," he said. "When they have a chance to play in front of a huge crowd, they basically have nothing to lose.
"I told him that he's going to be a great player, and I wish him all the best."
The former U.S. Open champion now plays Czech Bohdan Ulihrach in the second round.
