Nadal also became the first man in the Open era to win the same title 11 times -- 13 years after his first title here -- and moved one ahead of rival Novak Djokovic for career Masters titles.
"Eleven titles here, it's unbelievable. It's something difficult to imagine,'' said the 31-year-old Nadal, who won his first tournament here in 2005. "The history with this tournament is unique.''
It gave him a 76th title overall and ensured the Spaniard keeps his top ranking ahead of Roger Federer.
"To put another trophy in my museum, in my academy, is going to be something great,'' Nadal said. "This is one of the most important ones in terms of [my] personal feeling.''
Nishikori was chasing a first Masters title, but the Japanese player took 11 minutes to hold for 1-1.
He got some brief hope, breaking Nadal with a superb passing shot at full stretch to lead 2-1, but meekly surrendered the next four games.
"I knew it was going to be tough even though I was up break,'' said Nishikori, who complained of tiredness. "My legs were very heavy today, playing three sets [for] three days in a row [before the final]. It wasn't easy physically.''
The second set was a procession and Nadal won on his first match point with a stinging backhand winner.
Nadal's celebration was brief and low-key. He thrust both hands into the air, and then jogged over to offer Nishikori a sympathetic hug after beating him for the 10th time in 12 meetings.
Nishikori saved a set point with a sharp, angled volley at the net. But Nadal was in relentless mood and sealed it on his next chance with a crisp forehand winner.
"It's not easy to describe when you are coming back from injury and you start the clay-court season in this way,'' Nadal said.
Nishikori is still working his way back to form and full fitness, after missing the 2017 US Open and this year's Australian Open because of a torn tendon in his right wrist.
"It was a great week for me; I had an injury and couldn't play for a long time,'' said Nishikori, whose ranking has slipped to 36.
Nadal has not dropped a set in seven matches since coming back from a recurrence of a right hip injury that forced him to abandon during the fifth set of his Australian Open quarterfinal against Cilic.
The injury relapse subsequently forced him out of the Mexico Open and Masters tournaments at Indian Wells and Miami, but Nadal now looks back to his ruthless best on clay.
He has his sights firmly set on an 11th title at Barcelona next week and then an 11th French Open title at Roland Garros.