The 19-year-old seamer took five wickets in a losing cause as bat dominated ball in the series opener in Rawalpindi but missed the follow-up in Multan, where Ben Stokes' tourists took an unassailable 2-0 lead.
Pakistan were hopeful of having Naseem back to lead the attack when the final match begins on Saturday, but must now continue without him due to injury.
"A niggle in the bowling shoulder has ruled out Naseem Shah from the third and final Test between Pakistan and England in Karachi," the Pakistan Cricket Board confirmed.
"The fast bowler will travel to Lahore where he will undergo further assessment at the national high performance centre before beginning rehabilitation. The team management has not requested for his replacement at this stage."
Pakistan have already lost Shaheen Shah Afridi and Haris Rauf, leaving them with a makeshift pace attack.