The top-ranked Serb overcame some difficult moments before improving his record this season to 65-3.
Djokovic arrived on the court for the first time since Sept. 18 wearing a fright mask resembling rock star Alice Cooper the night after Halloween. Dressed all in black, Djokovic broke his Belgian opponent's first service game.
However, Malisse rallied against the U.S. Open champion in the second set and broke in the ninth game.
Djokovic then broke to a lead in the decider, and Malisse required a medical time out one game later after colliding with the umpire's chair when racing to retrieve a drop shot.
However, Djokovic failed to serve out the match at 5-3 and wasted a match point chance in the next game.
The Serb then quickly closed out the last two games to complete a 2-hour, 13-minute win.
Fish held serve in the opening game and lost the first point of the next game when he decided the pain in his left leg was too much to continue.
Fish is hoping to qualify for the season-ending ATP World Tour Finals for the first time. He stands in the eighth and final qualifying spot for the tournament starting in London on Nov. 20.
Although Fish cannot be overtaken this week, the last qualifying tournament is next week in Paris.
Tomas Berdych of the Czech Republic, sixth in the ATP points race, also missed an opportunity to improve his chances for a spot in London. The fourth-seeded Berdych was ousted by wild-card entry Kei Nishikori of Japan, who won 3-6, 6-3, 6-2.
After third-seeded Roger Federer's victory Monday, Switzerland had two more first-round wins.
Jarkko Nieminen of Finland fought back to beat Thomaz Bellucci of Brazil, 6-7 (5), 6-4, 6-3; Italy's Andreas Seppi edged Gilles Muller of Luxembourg 7-6 (4), 6-7 (5), 6-2; and Ivan Ljubicic of Croatia beat Frenchman Michael Llodra 7-5, 6-4.