The 14-time Grand Slam champion looked back to his healthy best after an injury-riddled 2016 as he beat the 49th-ranked Mayer 6-3 6-4 6-4 in just over two hours on Rod Laver Arena.
He will next play Cypriot Marcos Baghdatis in the second round. Last year Nadal was dumped out of the Open in the first round by compatriot Fernando Verdasco in a five-set boilover but there was no likelihood of a repeat ambush by Mayer.
"He doesn't have the typical game so he's going to the net. He changes a lot with different points," Nadal said of his German opponent.
"You need to be careful doing every single shot that he is hitting, so for me, it is a great victory and I'm very happy to keep having chances to play here in Melbourne.
"Today was a good first round for me. Florian is a tough first player to play against." Nadal is bidding to win his second Australian Open after beating Roger Federer for the 2009 crown.
But a left wrist injury plagued the Spanish left-hander after the French Open last year and he missed Wimbledon.
"I was healthy enough to practice the way I wanted to practice, so that's important for me and I was able to work a lot of things in Majorca and happy to be back," Nadal said.
"I've had a longer period of time here in Australia, it was a great experience and I was able to play in Brisbane."
Nadal took the opening set on his fifth set point with an ace and fought off Mayer to grab the second set.
His trademark never-say-die retrieving behind the baseline was a feature as he fought for every point. Nadal broke Mayer's service in the ninth game of the final set with a forehand winner and served out for a straight sets victory.