Djokovic claimed nearly 80 percent of the points on serve in a 6-0, 6-4, 6-4 pasting of Mayer. Djokovic won 25 of the 33 first-set points and had a total of eight unforced errors in taking the second and third sets.
Djokovic, seeded second this year, is a three-time defending champion in Melbourne. The two wins this year in Melbourne also give him 26 straight wins overall in ATP competition.
Heat has been one of the most discussed aspects of the tournament. With Wednesday's temperatures again well above the 100-degree Fahrenheit mark, players voiced concern about the safety of playing in such conditions. Heat-induced cramps led 32nd-seeded Ivan Dodig to retire from his match in the fourth set with a 6-4, 6-4, 3-6, 1-4 lead over Damir Dzumhur.
"You don't want to spend too much time in the heat," Djokovic said. "You want to try to win as quick as possible."
Temperatures are predicted to remain extremely high through Friday before a steep drop to the upper 60s during the weekend.
No. 3-seeded David Ferrer dropped his serve five times in the first and second sets before steadying his game for a 7-6 (7-2), 5-7, 6-0, 6-3 win over Adrian Mannarino. Seventh-seeded Tomas Berdych handled Kenny De Schepper 6-4, 6-1, 6-3 without facing a break point. Stanislas Wawrinka, seeded eighth, dropped his serve just twice in a 6-3, 6-3, 6-7 (4-7) 6-4 decision over Alejandro Falla.
Florian Mayer had the biggest upset of the day, knocking off 14th-seeded Mikhail Youzhny 6-4, 3-6, 6-3, 3-6, 6-3. Even though the match went five sets, Mayer and Youzhny completed it in a relatively quick 3 hours, 6 minutes.
Other seeded players losing Wednesday, in addition to Youzhny and Dodig, were No. 23-seeed Ernests Gulbis, who fell to Sam Querrey 6-2, 6-3, 6-4; and 30th-seeded Dmitry Tursunov, who was beaten by Denis Istomin 7-6 (7-3), 4-6, 6-1, 6-4.
Other seeded players advancing included No. 17 Tommy Robredo, 19th-seeded Kevin Anderson, No. 20 Jerzy Janowicz, 28th-seeded Vasek Pospisil and No. 29 Jeremy Chardy. Also winning a berth in the third round was Edouard Roger-Vasselin.