Over the course of history, disease has been one of the most common and important causes of death for humans. Additionally, epidemics have significantly contributed to population changes and civilizational decline. During the period of urbanization or the end of the Bronze Age, many archaeological sites in Iran and its surrounding lands tend to decline or be destroyed. Mesopotamian city-states, Minor Asia, Palestine, Egypt, and Harappan cities can all be seen as examples of this decline. In spite of the fact that archaeological evidence clearly demonstrates this decline, it is unknown what caused the decline. This study is based on a detailed review of historical sources and excavations conducted at sites associated with the Bronze Age and Iron Age, as well as a review and comparison of previous studies. There are records of epidemic diseases such as leprosy, tuberculosis, cholera, and the plague in Iran as well as neighboring areas, including Mesopotamia, Egypt, and the Indus Valley. At the beginning of urbanization, epidemic diseases were spread primarily as a result of the density of the urban population and the expansion of trans-regional communication networks. The transformation of endemic diseases into epidemics and pandemics requires a large, interconnected host community, which human societies did not possess prior to the expansion of transregional relations. As a result of transregional communication, disease and pathogenic agents were spread widely, including in Harappan cemeteries, where it has been proven that sick non-native people lived. A large part of the Bronze Age societies of Southwest Asia declined and sometimes were destroyed as a result of the change of the disease from a regional to a widespread pandemic.