His 6-3, 7-6 (3) victory came in one-hour and 34-minutes.
The Greek, who was appearing in his fourth final at this level, struck his forehands with fierce topspin and accuracy recovering just in time from failing to serve out the match at 5-4 in the second set to capture his first trophy of the season.
In a fast start, Davidovich Fokina showed the skills that helped him take down Djokovic early in the tournament to quickly find his range on his forehand from the baseline to earn an early break.
However, Tsitsipas quickly responded as he hit with greater depth, firing a forehand past the Spaniard to break back for 2-2.
The Greek continued to impose his heavy-hitting game on Davidovich Fokina, pulling the 22-year-old from corner to corner as he won four of the next five games to move ahead after 31 minutes.
Tsitsipas used all the momentum on his side to seize further control at the start of the second set as he overpowered Davidovich Fokina with his ball-striking.
The 23-year-old broke for a 2-0 lead, but Davidovich Fokina showcased the grit once again to soar back to 4-4.
Tsitsipas broke again when he received a bit of luck on breakpoint at 4-4 when his mis-hit forehand landed in before he won the point with a topspin forehand that the Spaniard was unable to return.
The Greek could not serve out the match though, with Davidovich Fokina raising his level to force a tie-break.
Tsitsipas would not be denied a second Masters 1000 crown however as he played more consistently in the tie-break forcing errors from Davidovich Fokina with his width to triumph.
The win moved Tsitsipas to 3-0 in his ATP Head2Head series with Davidovich Fokina.
Despite the defeat, Davidovich Fokina is projected to rise to a career-high No. 27 in the ATP Rankings following his dream run in the Principality.
With the win, Tsitsipas became only the sixth player to win back-to-back Monte Carlo titles in the Open Era joining Rafael Nadal (2005-12, 2016-18), Juan Carlos Ferrero (2002-03), Thomas Muster (1995-96), Bjorn Borg (1979-1980) and Ilie Nastase (1971-1973).
The third Tsitsipas overcame 2019 titlist Fabio Fognini, Laslo Djere, and second seed Alexander Zverev in straight sets, but survived a major scare in the quarter-finals against Diego Schwartzman, rallying from 0-4 in the third set to advance.
Another reward awaiting Tsitsipas for winning the Monte Carlo Masters is No. 2 ranking in the ATP Race To Turin.