Tomic, who was knocked out in the second round of the Washington tournament last week by eventual champion Juan Martin del Potro, complained of windy conditions but was more upset with his own lack of initiative after winning the opening set of the first-round encounter.
He will now have to hit the practise courts after missing a chance to build up some valuable hardcourt experience before the start of the US Open in three weeks.
The Australian number one, ranked 41st in the world, got off to a good start but could not maintain his form against the experienced German.
“I was up 5-2 in the first set and should have closed it out in the second,” said Tomic. “In the second set I didn’t start that well. My concentration dropped and he played well.”
Tomic managed only two aces and lost his serve four times.
“Florian is one of those guys who plays well once he gets his nose ahead,” he said.
“In the first set he was tight but in the second I missed my opportunities and didn’t focus very well – he took over then.”
World number one Djokovic has beaten Mayer in all five of their meetings including the first round of Wimbledon in June.
Croatian Ivan Dodig crushed Grega Zemlja of Slovenia 6-1, 6-1 to set up a meeting with the in-form Del Potro.