Malisse, who beat top seed Vince Spadea in Saturday's semi-final, continued his mastery of higher seeded players as he stopped the second-seeded Czech.
"It is a feeling that I've never felt -- seeing that last ball go out and getting the monkey off my back," said the 23-year-old, who had lost six previous finals appearances including two at Delray Beach.
Novak broke Malisse in the fourth game of the first set, but the Belgian broke back in the ninth game, handing Novak his first loss of serve since the first round. Malisse then stormed to a 4-1 lead in the tie-break before taking it 8-6.
In the second set, Novak double-faulted away the fourth game and Malisse claimed the title with his third break of the match.
"I told myself to keep holding my serve and that chances would come," Malisse said. "I got away with the first set but that's how sports goes. It's not over until you get the last point."
Novak said he thought Malisse coming back to win the first set was the key to the match.
"I had the lead, I was in control," said the Czech. "He was just better in the second set."
