"Everybody is dying", the pontiff decried, amid a recent increase in airstrikes on the besieged city.
Early on Wednesday morning it emerged that strikes have severely damaged two hospitals in the rebel-held area, leading to the death of two seriously ill patients.
The airstrikes hit the M1 and M10 hospitals, knocking out generators and cutting off water supplies - putting them temporarily out of service.
Mohammed Abu Rajab, head of M10 hospital -the largest of eight hospitals in eastern Aleppo - says two patients died because they could not be kept alive.
He says the intensive care unit was severely damaged.
Speaking at a public audience in St Peter's Square in Rome Francis said Aleppo was "an already martyred city, where everybody is dying".
He said everyone involved in the violence must "commit themselves with all their strength to protect civilians" and that this was "an imperative and urgent obligation".
"I appeal to the consciences of those responsible for the bombings, who will one day will have to account to God," the pontiff said.
Aleppo, Syria's largest city and former commercial centre, has been fiercely contested since rebels captured several eastern regions in 2012.
A Syrian military official in the capital, Damascus, said operations in Aleppo will continue until the "terrorists" in the eastern parts of the city are "wiped out".
