The 31-year-old triumphed despite suffering from an apparent muscle problem to became the lowest seeded player, at 13, to claim the title since Gustavo Kuerten in 1999.
Five weeks before the French Open kicks off at Roland Garros, Fognini produced some brilliant tennis on Monte Carlo's red clay to snatch his ninth ATP singles title.
Lajovic, who had not lost a set this week before Sunday, did not have the weapons to counter Fognini's tactical nous.
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Fognini made several unforced errors early on, allowing Lajovic to break in the third game. But the Serbian failed to capitalise as he dropped serve in the next game.
Fognini won three games in a row and held off Lajovic to seal the opening set with a stunning backhand winner down the line.
It was the first set Lajovic conceded in the tournament and the Serbian appeared quite shocked, dropping serve in the first game of the second set.
After a brief fightback Lajovic, who was also looking to win his first Masters title, was overwhelmed again and Fognini again broke to move 3-2 up.
In the following game, the Italian had his right leg strapped by the trainer and Lajovic tried to make the rallies longer.
But Fognini cleverly ended some of them with dropshots as he held serve for 4-2.
He ended the contest on his second match point.
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