Advancing to the third round with his 26th consecutive match win, Djokovic had a brief scare while serving at 3-0 in the first set when he turned over on his left ankle, tumbling to the court.
But it wasn't serious enough for him to warrant medical attention during the next break in play, and he took the opening set in just 22 minutes, conceding just eight points.
"It was just I slipped a little bit," Djokovic said. "It was an instant discomfort, but it was OK after."
With temperatures nearing 108 degrees Wednesday, Djokovic was asked about his retirement from a 2009 Australian Open quarterfinal against Andy Roddick due to a heat-related ailment.
"Obviously as the years go by, I'm more mature as a player, as a person," Djokovic said, explaining the differences in his condition between then and now.
"I learned new things in life. I develop myself. I'm physically ... stronger, mentally also. All of this plays, of course, an important role when you are playing in such conditions. Generally it's much more efficient for me nowadays to recover and to get ready for next point than it used to be (in) 2009."
Djokovic is attempting to win a fifth Australian title. He would be the first man to achieve that feat since the Open era began in 1968.
He will next play Denis Istomin on Friday.
Ferrer trailed 3-0 in the opening set before rallying in the tiebreaker, then fell behind 4-1 in the second before taking control in the final two sets.
Mannarino appeared to be more adversely affected by the hot temperatures and had a visit from the tournament doctor in the fourth set.
The Spanish baseliner has lost to Djokovic in the past two Australian Opens, in the semifinals last year and the 2012 quarterfinals.
Seventh-seeded Tomas Berdych was the first man into the third round with a 6-4, 6-1, 6-3 win over Kenny de Schepper of France.
Berdych took advantage of five of his eight break-point opportunities while maintaining a perfect 13-0 record on his serve. He set up his first match point with a deft half-volley at the net, then clinched it on the next when de Schepper hit a forehand long.
The 2010 Wimbledon finalist helped the Czech Republic repeat as Davis Cup champion last year, defeating Serbia 3-2 and going 4-1 in singles and 3-0 in doubles during the year.
Florian Mayer beat No. 14 Mikhail Youzhny, Uzbekistan's Denis Istomin beat No. 30 Dmitry Tursunov and Bosnian qualifier Damir Dzumhur advanced when No. 32-seeded Ivan Dodig retired with cramps while leading in the fourth set.
The Associated Press contributed to this report.