The Zayanderud Basin is an important agricultural area in central Iran. In the Basin, irrigation consumes more than 90 percent of the water used, which threatens both the downstream historical city of Isfahan and the Gavkhuni Wetland reserve—the final recipient of the river water. To analyze impacts of land use changes and the occurrence of metrological and hydrological drought, we used groundwater data from 30 wells, the standardized precipitation index (SPI) and the streamflow drought index (SDI). Changes in the wetland were analyzed using normalized difference water index (NDWI) values and water mass depletion in the Basin was also assessed with gravity recovery and climate experiment (GRACE)-derived data. The results show that in 45 out of studied 50 years, the climate can be considered as normal in respect to mean precipitation amount, but hydrological droughts exist in more than half of the recorded years. The hydrological drought occurrence increased after the 1970s when large irrigation schemes were introduced. In recent decades, the flow rate reached zero in the downstream part of the Zayanderud River. NDWI values confirmed the severe drying of the Gavkhuni Wetland on several occasions, when compared to in situ data. The water mass depletion rate in the Basin is estimated to be 30 (±5) mm annually; groundwater exploitation has reached an average of 365 Mm³ annually, with a constant annual drop of 1 to 2.5 meters in the groundwater level annually. The results demonstrate the connection between groundwater and surface water resources management and highlight that groundwater depletion and the repeated occurrence of the Zayanderud River hydrological drought are directly related to human activities. The results can be used to assess sustainability of water management in the Basin.