Drought is one of the most complex and threatening disasters, defined as a period of drier-than-normal conditions which results in water-related problems. In addition to climate variation, human activities can cause or intensify drought through groundwater overextraction, unsupervised expansion of agricultural lands, etc. One prime example of such drought has been observed in the Zayandehrud River basin in central Iran. We investigate the long-term (1986 to 2019) drought of the Zayandehrud River basin using meteorological, hydrological, and agricultural drought indices. The main focus of this research is to explore the impact of the irrigated area expansion in the upstream sub-basins on the agricultural drought of the downstream. To this end, different drought indices are employed over the whole basin and its sub-basins. The results indicate that the long-term precipitation index and snow reserves do not show a long-term trend during the study period, while the combined precipitation-evapotranspiration index and groundwater storage decline. The research concludes that the expansion of the agricultural lands in the river upstream, rising air temperature, and increasing population and industrial activities in the basin are most likely the driving forces to intensify the agricultural drought in the midstream and downstream parts of the basin.