The Serb has never lost before the quarter-finals at the tournament and is now just three victories shy of joining the 1,000 match-wins club.
“He probably has the biggest calf we have in tennis. Very strong guy, just solid from the baseline,” Djokovic said of the 35th-ranked Karatsev.
— Novak Djokovic (@DjokerNole) 1652198683000
“You never know with him. If he’s feeling the ball, he can be very dangerous because he stays so close to the line, puts pressure on his opponents.”
Karatsev committed 36 unforced errors during the match and Djokovic made sure to capitalise on those mistakes.
“He was missing a lot of points today though, gave me a couple of breaks there in the first and second.
“I’ll take this win for sure. It’s a straight-sets win against a quality opponent and I’m looking forward to the next challenge,” continued the Serb.
Djokovic, who is in his record-extending 369th week as the world number one, must reach at least the semi-finals in Rome to hold onto his top ranking, and avoid being overtaken by Daniil Medvedev.
In the last 16, Djokovic will face compatriot Laslo Djere or three-time major champion Stan Wawrinka.
Djokovic started with a break of serve en route to a 2-0 lead but Karatsev erased his deficit in no time to draw level.
The top seed upped the pressure to break again in the eighth game and closed out the set in style, showing off his volleying skills in front of a buoyant Rome crowd.
Djokovic raced to a 4-0 advantage in the second set and sealed the 90-minute victory on his first opportunity, to improve to 2-1 in his head-to-head against Karatsev.
Grigor Dimitrov and Stefanos Tsitsipas will square off for the second time in seven days after the Bulgarian moved past American qualifier Brandon Nakashima 6-3, 6-4 in first round action on Tuesday.
It was Dimitrov’s 10th Masters 1000 match-win of the season and he’ll be searching for just a second victory over Tsitsipas in their sixth career meeting against one another.
Argentina’s Diego Schwartzman saved two match points and recovered from a 15-point losing streak during his clash with the in-form Miomir Kecmanovic before punching his ticket to the second round with a 6-2, 3-6, 7-6 (7/3) result. The 12th seed will face lucky loser Marcos Giron next.
British ninth seed Cameron Norrie saved 4/4 break points in his 6-4, 6-4 success over local wildcard Luca Nardi and will next play former US Open champion Marin Cilic.
In the women’s tournament, Madrid finalist Jessica Pegula enjoyed a winning start to her campaign, squeezing past world number 25 Liudmila Samsonova 4-6, 6-3, 6-4 to advance to the second round.
A runner-up to Ons Jabeur in the Spanish capital on Saturday, Pegula withstood 38 winners off from the big-hitting Samsonova to set up a last-32 showdown with in-form Ukrainian Anhelina Kalinina.
The 13th-seeded Pegula, who played with a heavily-strapped left thigh against Samsonova, made the quarter-finals in Rome last season and has improved her 2022 win-loss tally to 18-9.
Former French Open champion and number 11 seed Jelena Ostapenko was sent packing by American qualifier Lauren Davis 6-2, 6-3 in just one hour and 10 minutes.
American world number 32 Amanda Anisimova, a former Roland Garros semi-finalist, will take on Olympic champion Belinda Bencic in the next round after recovering from a second-set bagel to overcome Czech qualifier Tereza Martincova 6-2, 0-6, 6-4.