Expanding negative impacts of human activities on ecosystem integrity, often resulting in their destruction, are one of the key environmental issues facing mankind, highlighting the need to assess and control such destructive trends. To reduce these impacts, it is critical to monitor ecosystem health using quantitative and qualitative indicators to examine changes over time. This study aims to assess the health of Zayandehroud basin using the DPSIR Framework and the synthesis of Remote Sensing and GIS. Fourteen environmental and socio-economic indicators were selected to determine the ecosystem health of the basin, with their weights being calculated based on the Analytical Hierarchy Process. Furthermore, spatio-temporal changes of the ecosystem health over 27 years (1993–2020) were analyzed to measure ecosystem pressure, status and response. The results showed an increase in areas with moderate health classes during this period. Although the areas between the center and the east of the basin were fragile, the average ecosystem health status of the west section is better than other areas. In other words, the health of western Zayandehroud basin has improved over time, while it has deteriorated in the eastern and central basins. The results provide policymakers and managers with information on the main drivers of change, such as population growth, land-use change, and infringements on the riparian sections of the river. Opportunities are provided for responses which will reduce negative impacts on the health of the river basin and their communities. The linking of different ecological and environmental components in a logical hierarchical form provides significant knowledge on changes in ecosystem health over time.

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