High roller: Rising Russian star Medvedev stuns Djokovic in Monte Carlo
Medvedev, 23, saw off the 15-time Grand Slam winner 6-3, 4-6, 6-2 to claim the biggest victory in his increasingly impressive career.
Medvedev broke number one seed Djokovic five times on his way to victory, setting up a semi-final clash against world number 48 Dusan Lajovic – also from Serbia.
The Russian 10th seed beat much-fancied Greek youngster Stefanos Tsitsipas in the previous round, and on Friday gained a measure of revenge for his defeat to Djokovic in the last of the Australian Open earlier this year.
Moscow-born Medvedev is currently ranked 14 in the ATP standings, and is aiming to win a fifth career title.
Elsewhere in the draw, defending champion Rafael Nadal plays Guido Pella of Argentina on Friday, as the Spanish clay court king aims for a 12th title in the principality.