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The Ganges Delta in Bangladesh is an example of water-related catastrophes in a major rural river basin where limitations in quantity, quality, and timing of available water are producing disastrous conditions. Water availability limitations are modifying the hydrologic characteristics especially when water allocation is controlled from the upstream Farakka Barrage. This study presents the changes and consequences in the hydrologic regime due to climate- and human-induced stresses. Flow duration curves (FDCs), rainfall elasticity, and temperature sensitivity were used to assess the pre- and post-barrage water flow patterns. Hydrologic and climate indices were computed to provide insight on hydro-climatic variability and trend. Significant increases in temperature, evapotranspiration, hot days, heating, and cooling degree days indicate the region is heading toward a warmer climate. Moreover, increase in high-intensity rainfall of short duration is making the region prone to extreme floods. FDCs depict a large reduction in river flows between pre- and post-barrage periods, resulting in lower water storage capacity. The reduction in freshwater flow increased the extent and intensity of salinity intrusion. This freshwater scarcity is reducing livelihood options considerably and indirectly forcing population migration from the delta region. Understanding the causes and directions of hydrologic changes is essential to formulate improve water resources management in the region.