Weather and climate have been participating in an imperative function in both the expansion and crumple of mankind civilizations diagonally across the globe ever since the prehistoric eras. The Neolithic Mehrgarh (ca. 7000–2500 BC) and Balochistan and Indus Valley civilizations (ca. 2500–1500 BC), in Sindh Province in Pakistan, have been the spotlight of explorations to historians, anthropologists, and archeologists in terms of their origin, development, and collapse. However, very rare consideration has been given previously to the role of weather and climate, sanitation, and wastewater technologies in highlighting the lessons of these formerly well-developed ancient metropolitan civilizations. This study presents an existing climate of the archaeological sites, sanitation, and wastewater technologies to recognize the different elements that influenced the evolution of the civilization mystery. In addition, it is recommended that the weather and climate conditions in southwest Asia were the foremost controlling element in resolving the destiny of the Indus and Mehrgarh civilizations. Furthermore, the rural tradition was mostly adapted by the increasing rate of western depressions (winter rains), as well as monsoon precipitation in the region. The factors that affected the climate of both civilizations with the passage of time might be population growth, resource conflicts, technological advancement, industrial revolution, Aryan invasion, deforestation, migration, disasters, and sociocultural advancement. The communities residing in both civilizations had well developed agriculture, sanitation, water management, wells, baths, toilets, dockyards, and waterlogging systems and were the master of the water art. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.