.Three-times major winner Murray was set to face Djokovic for the 37th time in a highly anticipated clash on clay at the ATP Masters 1000 event in the Spanish capital.
."Unfortunately, Andy Murray is unable to take to the Manolo Santana Stadium due to illness," organisers wrote on Twitter.
Andy Murray has withdrawn from his last-16 match against world number one Novak Djokovic at the Madrid Open on Thursday due to illness, tournament organisers said.
Three-times major winner Murray was set to face Djokovic for the 37th time in a highly anticipated clash on clay at the ATP Masters 1000 event in the Spanish capital.
"Unfortunately, Andy Murray is unable to take to the Manolo Santana Stadium due to illness," organisers wrote on Twitter.
"Instead, Andrey Rublev and Daniel Evans will open the day's play on centre court."
Former world number one Murray, who had earlier said he would skip the claycourt season in order to protect his fitness, accepted a late wildcard in Madrid and beat Dominic Thiem and Denis Shapovalov in his opening two matches.
Meanwhile, Tunisia's Ons Jabeur moved into the first WTA 1000 final of her career when she beat Russian qualifier, Ekaterina Alexandrova, 6-2 6-3 at the Madrid Open on Thursday.
Alexandrova held a 6-1 head-to-head record against eighth seed Jabeur but it was the Tunisian who showed flair and impeccable court coverage to get the better of the qualifier.
"I felt like I was sick of losing against her all the time. So I came here to take my revenge," Jabeur said in a post-match interview.
"I feel like this tournament is a revenge tournament, every match. I'm very glad with my performance. I know she plays really well, so I tried to really impose my rhythm. I'm very happy with the level I played with today."
The pair traded breaks in the opening set but Jabeur stepped up her game to break Alexandrova at 3-2, breaking with a lob at the net.
Jabeur let out a scream of elation as the crowd got to their feet and the 27-year-old did not look back, breaking four times in the match to wrap up the contest in 61 minutes.
She will play either American Jessica Pegula or Swiss Jil Teichmann in Saturday's final.
"I really hope they play for five hours and they become tired," Jabeur said with a laugh.
"I'm just going to focus on myself, it's been tough losing a few finals lately. I'm going to do my best and then give it all for this one."