The 31-year-od Fognini set himself up for the title on Saturday with his stunning 6-4, 6-2 victory over Nadal to end the Spanish star's 25-set win streak in the principality.
The last Italian to win here was Nicola Pietrangeli in 1968.
Fognini becomes the first Italian to win a Masters 1000 singles title and is the oldest Monte Carlo champion in the open era. So when that happens, you have to lose.
"So I knew I had nothing to lose, because of course, especially when you're with him on clay, it's always really tough".
"No, was a bad feeling. I am coming from low moments in terms of injuries, and in terms of the mental side have been not easy to accept all the things that have been going on during the last times", Rafael Nadal said.
Nadal, an 11-time victor of the event, rallied from 4-1 down in the opening set before finally overhauling Argentina's Guido Pella 7-6 (7/1), 6-3.
"Novak played worse here than the times before", Medvedev said.
On every one of those he was a favourite, yet lost to Aljaz Bedene, Jaume Munar, Felix Auger-Aliassime and Jiri Vesely, taking just one set in the process, and on Twitter earlier, I put a poll up asking what Fognini's SP would have been if this match took place in round one at this time last week.
Fognini broke for a 3-2 lead in the second set when Lajovic hit a forehand wide. Start to breathe. I know that it's hard sometimes for me.
The 10th-seeded Medvedev could not hold the pace as winds swept across centre court and Lajovic quickly moved 4-0 up in the second set against a frustrated opponent, who bowed out on the second match point.
"And after that, I say, Okay, I mean, I'm here, 3-1". And after one year and a half, without having the chance to play tournaments in a row and a lot of stuff happened, is more hard to hold sometimes the level every single day when you don't have confidence in tournaments in a row, no, or matches in a row.
There's no match history between these two players.
"I had the worst nightmare, falling down 5-1".
Nadal is usually the undisputed crowd favorite on the French Riviera, but shouts of "Fabio, Fabio, Fabio" rang out at the Monte Carlo Country Club.