The Italian No.8 seed, who had won back-to-back grass titles during his Wimbledon preparations, said he was "heartbroken" to have to miss out. "The dream is over for this year but I will come back stronger."
The Spaniard showcased his trademark fighting spirit to overcome a tricky test from Francisco Cerundolo, advancing 6-4, 6-3, 3-6, 6-4 after three hours and 36 minutes.
Centre Court and Court 1 at the All England Lawn Tennis Club are both fitted with a roof, meaning their schedules will commence as planned regardless of the weather.
Second seed Rafael Nadal will play Argentina's world number 42 Francisco Cerundolo in the first round while young sensation Carlos Alcaraz will take on Germany's Jan-Lennard Struff.
The reigning Indian Wells champion Taylor Fritz added his second title of the season to his list of accolades after defeating Maxime Cressy 6-2, 6(4)-7, 7-6(4) in an all-American battle.