The persistent presence of the plague, following the first wave of the Black Death in the 14th century AD, continued to affect human societies. In the 15th century, this disease had destructive effects on the social situation of the cities of Herat during the Timurid period and Cairo during the Mamluk era, as they were administrative centers of government and centers of various social classes. The present research, employing a descriptive-analytical approach, aims to compare the social consequences of the disease in these two cities. The findings of this study show that, despite the absence of a well-equipped hospital like the one in Cairo, Herat suffered less devastation from the disease due to the construction of a hospital after estimating the plague casualties and its geographical extent. The mortality rate in Herat was significantly lower, and its population structure underwent fewer changes. This is because Herat had recently been chosen as the capital under Shahrukh’s rule, which led to a transition from a nomadic to a settled lifestyle, resulting in a lower population density than Cairo. Herat’s mountainous climate and limited trade accessibility through land routes made it less susceptible to recurrent disease outbreaks and their enduring adverse effects. Conversely, Cairo’s hot, humid climate, flourishing maritime trade, and dependence on land and agriculture contributed to its economic recession during the plague. The economy of Herat, still a young city in the 15th century, was less vulnerable to economic recession due to the plague.