Novak Djokovic would only make it to the finals of the tournament played at the Novak Tennis Center in the Serbian capital Belgrade.
But in the semifinals he encountered patrol.
The 27-year-old Karatsev took home the first set and looked to be on his way to two straight when he led 4-2 in the second, but then the world set turned around and won the set 6-4.
Karatsev showed an impressive calm throughout the match and it was really needed in the end when he saved a full ten break balls.
In total, he saved an impressive 23 of 28 break balls.
The set numbers were written 7-5, 4-6, 6-4 and the match took a full three hours and 25 minutes.
It is the longest match on the ATP Tour in 2021.
Karatsev now meets the winner of the match between Matteo Berrettini and the Japanese Taro Daniel in the final.
Loss a little over a week ago
The loss comes just over a week after the Serb was knocked out of the ATP tournament in Monte Carlo by Briton Daniel Evans, ranked 26th.
Djokovic won his 18th Grand Slam title when he won the Australian Open in February, but that form seems to be blown away.
Several other top-ranked players have also participated in another ATP tournament in Barcelona.
There, Rafael Nadal and Stefanos Tsitsipas will meet in the final tomorrow.