The Serbian was in irresistible form early on and appeared keen to seal a quick success in the scorching Melbourne heat by winning the opening eight games of the match.
While world number 98 Mayer did at least improve thereafter, he never threatened an upset and failed to earn a single break point as Djokovic completed a 6-0 6-4 6-4 win in 107 minutes.
Djokovic, who is bidding to become the second man after Roy Emerson to win four straight titles here, came storming out of the blocks.
The second seed, under the watchful gaze of new coach Boris Becker, broke at the first opportunity and it quickly became apparent there would be few alarms.
Indeed, the greatest concern came when Djokovic fell going for a volley, but the 26-year-old did not appear to be in any distress as he 'bagelled' Mayer inside 22 minutes.
Djokovic immediately secured his fourth break of the match at the start of the second set and although Mayer managed to stop the rot on his next service game, he could not make any impact on his opponent's serve and duly found himself two sets down.
Mayer held his own in the final set and had not faced a single break point as he went 4-3 in front.
But Djokovic showed his experience by attacking Mayer's next service game and the Argentinian double faulted at the wrong time to give the six-time grand slam champion the chance to serve for the match.
Djokovic wrapped up victory at the second attempt when Mayer put a forehand long to set up a clash with either 30th seed Dmitry Tursunov or Denis Istomin.