After dropping the first set 4-6, the tournament's No. 3 seed captured the second and third sets by identical scores of 6-3, 6-3.
The victory was worth $558,000.
"I tried to stay focused all the time, because the role of the favorite in these kind of big matches is not easy to cope with," Djokovic said. "I didn't think that I'm going to play in the finals against a player who's unseeded, but obviously he deserved to be there. He showed his quality."
Wawrinka, from Switzerland, was trying to become the second unseeded champion in Rome in the Open Era. Spain's Felix Mantilla topped Roger Federer in the 2003 final.
Wawrinka's lone tournament title came at Umag, Croatia, in July 2006.
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