Top seed Nadal, who is also targeting an 11th Roland Garros trophy this year, extended his run of consecutive sets won on clay to 36 after recording the win in an hour and 33 minutes.
The Spaniard’s record 31st Masters title also ensured he retained the world number one ranking ahead of rival Roger Federer.
Nadal returned to action in the Davis Cup this month after recovering from a leg injury which forced him to retire in the Australian Open quarter-finals in January.
“I want to thank all my team and my family. We had some tough moments during the last five months after a couple of injuries in a row,” Nadal said.
“It’s always special for me to be back here, having this trophy. It’s one of the most important events of the year for me.”
Nishikori, who missed a large part of last season with a wrist injury, grabbed an early break in the Monaco sunshine before his 31-year-old opponent won four games in a row to take control of the match.
Nadal took the opening set with a blistering forehand and went on to convert two breakpoint opportunities in the second to lift the title.
Despite the defeat, world number 36 Nishikori will take plenty of positives from the tournament as he continues to work his way back to form and full fitness.
Nadal and Nishikori will next feature at the Barcelona Open, which begins on Monday.
Reporting by Hardik Vyas in Bengaluru; Editing by Clare Fallon