The Serb did not need to be at his brilliant best to dispatch the world number 29 who laboured to stay in the encounter, but never looked like troubling his opponent.
Djokovic broke decisively in the 10th game of the first set and then sprinted through the second on fast forward.
Mayer held on to the Serb's coat tails in the third, but Djokovic broke in the ninth game and finished him off with an ace to set up a mouth-watering semi-final against Roger Federer [ Images ], who ruthlessly dismantled Mikhail Youzhny 6-1, 6-2, 6-2 to reach the semi-finals for the eighth time.
"It took me a while to get used to the conditions, having played my last three games indoors," Djokovic said in a courtside interview.
"It was a little windy, but I'm satisfied with the overall performance. Florian had some opportunities to come back in the third set, as well as chances in the first, but I held my nerve at the important moments.
"It's always a pleasure playing against Roger, so I'm looking forward to that," Djokovic said.
"He's been so dominant and consistent in Grand Slams, it's the ultimate challenge on a grass court."
Third seed and six-times champion Federer was at his imperious best on Centre Court against the 26th-seeded Russian, picking him off at will.
"I thought I played great out there today," Federer said in a courtside interview after a 14th successive win over Youzhny. "My game maybe suits up well against his.
"He was down in all the sets rather quickly. I am extremely happy to be back in the semi-finals here at Wimbledon."
"I think it's inspiring when royalty and other legends of the game come to watch," Federer said. "It's great for tennis."
Federer, knocked out in the quarter-finals at the All England [ Images ] Club the last two years, roared into a 4-1 lead and after a short rain delay wrapped up the first set in 28 minutes.
The Swiss maestro broke in the first game of the second set with the aid of a lucky net-cord and, showing no sign of the back injury which hampered him in his quarter-final win over Xavier Malisse, he sauntered into a 2-0 lead.
With the sun making a rare appearance at the tournament, Federer broke Youzhny again at the start of the third set.
The Russian let out a huge roar of frustration when he failed to take advantage of a break-point but he made far too many unforced errors to get back into the match.
Federer wasted three match points on Youzhny's serve but he quickly earned himself two more and took the first with a deft angled volley to wrap up victory in an one hour 32 minutes.