The fifth seed stayed composed when it mattered to eventually run down his opponent and claim the most prestigious title of his career.
Rublev was 4-1 down in the decider but ground his way back into the contest to prevail on his second match point with an ace at a sun-drenched Monte Carlo Country Club.
It was Rublev's third attempt in a Masters final after failing at the final hurdle here in Monte Carlo and in Cincinnati in 2021.
"I don't know what to say, I'm just happy, I struggled so much to get this title," said Rublev.
Rune, who burst into the limelight at last year's French Open when he reached the quarter-finals, needed nearly three hours to beat Italian Jannik Sinner (21) in the semi-finals.
Rublev also needed three sets to beat American Taylor Fritz (25), and fatigue was a factor in Sunday's showdown.
Rune, the youngest Monte Carlo finalist after Rafael Nadal (36) in 2005, opened a 4-2 lead in the first set on his second opportunity to break, only for an unforced forehand error to allow Rublev to break right back.
The Russian, however, bowed under pressure in the seventh game as he sent a forehand long to lose his second service game and give Rune the opening set.
After an early exchange of breaks, Rune netted a routine shot to drop serve again before Rublev held for 4-2 in the second set.
The Russian then broke to love and levelled the contest on serve as Rune seemed to lose his composure.
The Dane, however, found gravity-defying angles to break first in the decider, moving 3-0, and 4-1 ahead.
But Rublev did not surrender and after breaking in the seventh game, he broke Rune's serve again as the Dane received a warning for angrily sending the ball into the crowd in the 11th game.
