This study examined changes in Iran’s river flows by applying regression and analysis of variance methods to long-term ground-truth data. Evaluations were performed for the country’s data-rich rivers, covering almost 97% of all rivers and including more than 35 years of measurements. The results showed that about 56% of Iran’s rivers have experienced a negative trend in mean annual flow that is approximately 2.5 times greater than that reported for world’s rivers, leading to a shift from perennial to intermittent for about 20% of rivers in Iran’s sub-basins. This reflects surface freshwater shortages in Iran caused by natural and, more importantly, anthropogenic disturbances. It may even indicate the development of new hydrological regimes which can have significant implications for future surface water storage in Iran. This research improves understanding of changes in Iran’s river flows and provides beneficial information for sustainable water resources management in the country.