Alcaraz, ranked No.2, withdrew from the Barcelona Open in midweek after undergoing a test on his right wrist, and the fourth-ranked Djokovic is nursing a shoulder injury.
Alcaraz said on Friday that it "hurts" to announce that he will miss the Madrid Open for a second straight year. The tournament starts on Monday.
Alcaraz's withdrawal in Barcelona came a day after he called for a trainer and had his wrist treated during his opening match, a 6-4, 6-2 victory over Otto Virtanen.
Djokovic has not competed since the BNP Paribas Open in Indian Wells. He missed the Miami Open because of a right shoulder injury and also skipped the Monte Carlo Masters.
"Madrid, unfortunately I won't be able to compete at the Madrid Open this year," he wrote on his social media accounts on Friday. "I'm continuing my recovery in order to be back soon. Hasta pronto!"
Djokovic is a three-time champion in Madrid.
The tournament said in a statement: "We hope to see you back here as soon as possible so we can enjoy your tennis as we have done so many times in the Caja Mágica."
Alcaraz and Djokovic's next tournaments are the Italian Open and the French Open, both won by the Spaniard last year.
Home favourite Alexander Zverev held his nerve to beat Francisco Cerundolo and book a semi-final spot at the Munich Open.
The top seed and defending champion recovered after letting slip a double break lead in the first set to claim a 5-7 6-0 6-2 win.
He now faces Flavio Cobolli, who cruised to a 6-2 6-2 victory against Vit Kopriva.
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