Popyrin, a 25-year-old Australian who began the event ranked 62nd in the world, collected the third singles title of his career, his first in a Masters 1000 event - the tournaments classified just below the Grand Slam events.
His surge through to the Montreal title included three victories over top-10 players.
"It means the world, for all the hard work I've put in over the years, all the sacrifices I have made," Popyrin said.
"Not just me, but my family, my girlfriend, my team, everybody around me. They have sacrificed their whole lives for me and for me to win this for them is just amazing."
The result will vault Popyrin's ranking to 30. That's just behind the career-best 23 that Popyrin held after he upset Rublev, a 26-year-old Russian, in the third round at Monte Carlo in April.
Only three players were ranked lower than 62 when they won Masters 1000 tournaments - Croatia's Borna Coric (then 152 at Cincinnati in 2022), Spain's Roberto Carretero (then 143 at Hamburg in 1996) and Sweden's Mikael Pernfors (then 95 at Montreal in 1993).
The result ends a lengthy drought for Australian players in Masters 1000 tournaments, as Lleyton Hewitt last prevailed at Indian Wells in 2003.
Popyrin rode his serve to the victory over Rublev. The Aussie had a 10-4 edge in aces, won 84 per cent of his first-serve points (compared to 63 per cent for the Russian) and saved five of the six break points he faced.
"I tried to focus on what I had to do on my serve," Popyrin said, according to AFP.
"My first two match points, I didn't make a first serve, but on the third, I did what I felt I needed to do. I hit a pretty solid forehand to win it."
Cincinnati Open
Tenth-seeded Tommy Paul of the United States was knocked out in the first round at Mason, Ohio, squandering three match points and falling 6-2, 4-6, 7-5 to Italy's Flavio Cobolli.
Paul led 5-4 in the third set and three times had the opportunity to end the match on Cobolli's serve. However, Cobolli rallied to win that game, then took a 6-5 edge by converting his fourth break point of the next game before serving out the match.
Two weeks ago, Cobolli advanced to the tournament final in Washington.
In the day's only other match, Russia's Karen Khachanov routed Argentina's Francisco Cerundolo 6-0, 6-3.
