He led by a break twice and missed a host of routine short-court forehands in the breaker while failing to convert three set points. He hit a superb forehand down the line but Djokovic stretched himself for a lunging backhand volley that gave him a crosscourt victor, and a chance to fight a few other points.
He may have had to call two medical timeouts for a neck and right leg injury, but chance after chance was squandered.
He might want to re-assess, after he downed 12-times major victor Novak Djokovic on Tuesday to become the first Italian man to reach a Grand Slam semi-final in 40 years.
His opponent, however, was the stronger in an epic fourth-set tiebreak, prevailing 6-3 7-6 (4) 1-6 7-6 (11) on his fourth match point after more than three hours of high-octane tennis.
"A hard one to swallow", a glum Djokovic acknowledged during a brief news conference, in which he delivered clipped answers and said he might not play during the upcoming grass-court season.
"I was a bit unlucky not to capitalize on the second set", said Djokovic, who improved to 7-1 against Bautista Agut.
Cecchinato (it's pronounced cheh-key-NAH'-toe) came through on his fourth match point, looping in a backhand return victor as Djokovic tried to surprise him with a serve-and-volley attempt.
Cecchinato is the lowest-ranked French Open semifinalist in 19 years and the first Italian man to make it that far at any major in 40 years.More news: Lions, tigers, jaguar on the loose at German zoo; bear shot
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Told in an on-court interview that he wasn't dreaming, Cecchinato responded: "Are you sure?" Eventually, the Italian Olympic Committee announced that sanctions were dropped on a technicality.
Three-time champion Williams is playing her first Grand Slam tournament since taking time off last year due to pregnancy, while Sharapova is at Roland Garros for the first time in three years after serving a doping ban in 2016 and being refused a wildcard 12 months ago.
"To be able to win that first set and get ahead was crucial". Cecchinato held on, played some exquisite line shots and at the end, as Djokovic raced close to the net, the Italian lobbed the ball from his backhand towards the baseline and re-wrote history.
American 13th seed Madison Keys reached the quarter-finals for the first time with a 6-1, 6-4 win over Romania's Mihaela Buzarnescu.
And Djokovic woke up, blazing through the third set as Cecchinato looked out of sorts.
But German second seed Alexander Zverev is through, having saved a match point and survived a second successive scare on Friday, coming back to defeat Bosnia's Damir Dzumhur in five sets to reach the fourth round for the first time.
Cecchinato will now face Dominic Thiem, who defeated Alexander Zverev earlier. "Because now I need to realize the moment, because I will play the semi-final in Roland Garros".