The top-ranked Nadal beat the unseeded Greek upstart 6-2, 7-6 (4) for his fourth Rogers Cup crown and fifth victory of the year. He has 33 ATP World Tour Masters 1000 titles.
"If you told me this two weeks ago, I would not have believed it,'' Nadal said. "It's a great way to start the hard-court season. Winning in Toronto is so important. You don't win Masters 1000s very often. It's a very important victory for me and I'm very happy."
The 32-year-old Spanish star also won the Rogers Cup in Toronto in 2008 and in Montreal in 2005 and 2013.
"I'm very happy to have this trophy with me again,'' Nadal said. "It means a lot. It has been a fantastic week, a very positive one.''
Nadal later announced that he would skip a Masters tournament in Cincinnati this week to rest and get ready for the US Open.
"No other reason than personally taking care of my body and trying to keep as healthy as I feel now,'' Nadal said in a statement.
And so a "Big Four'' reunion will have to wait for at least a few more weeks. Nadal, Roger Federer, Novak Djokovic and Andy Murray haven't played in the same tournament in more than a year. The other three are scheduled to play in Cincinnati this week.
Nadal's win Sunday was notable. His previous four titles this year came on clay at the French Open, Monte Carlo, Barcelona and Rome. He also beat Tsitsipas in in the Barcelona final.
"He was normal like all of us and he managed to become this beast, this monster that he is today,'' Tsitsipas said. "It's true ... that's how you feel when you play against him. I need to work much more and hopefully I can reach his level one day.''
Nadal overcame a late service break and fought off a set point at the Aviva Centre. He converted his first match point of the tiebreaker to end it.
"He never cracks,'' Tsitsipas said. "He will always grab you like a bulldog, and he will always make you suffer on the court.''
Tsitsipas reached the final by becoming the youngest player to beat four straight top-10 players in an event since the ATP World Tour was established in 1990. He began the run against seventh-seeded Dominic Thiem, then knocked off No. 9 Djokovic, No. 2 Alexander Zverev and No. 4 Kevin Anderson.
Tsitsipas will jump from 27th to 15th in the world on Monday.