Djokovic, a two-time runner-up against Nadal in previous years, ensured that it was a case of third time lucky as the second seed recovered from a set deficit to seal a hat-trick of ATP Rome Masters titles.
Nadal, who was bidding to improve on his record haul of seven, cruised into a 4-1 lead before eventually claiming the opening set 6-4.
The Serb, who needed some three hours to get past Milos Raonic on Saturday, showed no sign of physical or mental fatigue in the second set, however, as Djokovic looked good to level up the match by cruising into a 3-0 lead.
Top seed Nadal battled back to move within one game of parity, but the world number two kept his nerve to see out the set by a 6-3 margin.
The 26-year-old then picked up where he left off by breaking the Spaniard's serve en route to a three-game lead in the final set.
Nadal pegged him back to three apiece, but the resurgence only served to inspire Djokovic, who won three successive games to down the 27-year-old.