Abstract: Significant anthropogenic impacts and climate change are putting the hydro-ecological conditions in river systems at risk of deterioration. It is crucial to record long-term trends for both an objective assessment during the planning process and the development of a methodological basis for further scientific investigations. This article analyzes human pressure and changes in the hydro-ecological status of the Chepelarska River (Southern Bulgaria), making recommendations for its improvement. The study relies on long-term hydrological data about registered runoff for 74 years from 1950 to 2023, information regarding hydro-morphological changes (regulated river sections and constructed hydropower plants), and dataset from monitoring of biological (phytobenthos, phytoplankton, fish fauna, macrophytes, and macrozoobenthos), physicochemical (pH, DO2, BOD5, Total N, Total P, NH4, NO3, NO2, and PO4), and specific chemical (Al, Cd, Cu, Pb, Mn, and Zn) water quality elements collected for 14 years between 2010 and 2023. The resulting information show a rising variability of runoff and a statistically significant tendency toward a flow volume decline, increasing morphological pressure from hydropower construction and aquaculture farming, and despite the overall positive hydro-ecological trend – constant deviations in some biological (macrozoobenthos), physicochemical (Total N, Total P, NH4, NO2, PO4), and specific chemical (Cd, Mn, Pb, Zn) water quality elements. The achievement of better hydro-ecological conditions requires the application of a complex of environmental, engineering, and legislative measures.