This study detects changes in hydrologic drought indices (HDIs), including magnitude (i.e., daily mean, low flows, and flow quantiles), variability (i.e., coefficient of variation), and duration, at 22 stations over Isfahan province and Zayandehrud basin, Iran by nonparametric Mann–Kendall tests. The results indicate a decreasing trend for average, low-flow indices (1, 7, 15, 30, and 90 days), and flow quantiles (q25, q75, q95, and q99). The decreasing trend of low-flow indices is observed for both arid and humid territories. However, streamflow variability and duration show both negative and positive trends, in which stations with positive trends are more frequent than those with negative trends. The subbasins of Zayandehrud Dam, which provides water for agriculture, houses, and industry, also show negative trends for low-flow magnitude and positive trends for drought duration. These results indicate an increasing water-supply deficit for a large semiarid region and an increasing drinking water deficit for a number of metropolitan cities in this region of Iran. In addition, considering other types of water resources, such as ground water table, and water demands, such as agricultural water use, this increasing risk can be attributed to anthropogenic effects, although more evidence and study is needed to prove this.