In the Anthropocene, human activities have created unprecedented changes and nonlinear relationships between humans and nature. These changes can be much faster and more intense in arid and semiarid areas that have been affected by intense human activities. Iran has climates from very humid to very dry, but arid and semiarid climates cover the country's largest area. Many of these arid areas have undergone severe changes in their surface and groundwater ecosystems in recent years, which have caused severe damage to humans and the environment in the area and surrounding areas. Therefore, in this study, using the theory of regime shifts, the time series of the Zayandeh‐Rud River Basin in the center of Iran were analyzed. First, the data of the desired time series in the period of 1986–2018 was arranged seasonally. Then, using the sequential t‐test method, regime shifts in these time series were identified, and then, causal loop diagrams of these shifts and their drivers and feedbacks were interpreted. The results showed that in the time series of quantity and quality of surface water and groundwater level in the studied stations and aquifers, regime shifts can be identified. Regime shifts were also identified in the time series of agricultural land area. These shifts have occurred with the increase in human activities since the early 1950s in the metropolis of Isfahan, the increase in agricultural and industrial exploitation, and consequently, the increase in population. When this reinforcing feedback loop becomes dominant, the Zayandeh‐Rud River system has shifted from a regime of rich water resources to a regime of poor water resources. However, by recognizing and systematically analyzing these shifts, the Zayandeh‐Rud River system can be directed toward a sustainable system through structural reform, negotiation, and redefining goals.