Riparian ecosystems are among the most impacted by human activities despite their great importance as refuges for biodiversity and providers of environmental services. The Nazas River is one of the most important wetlands in north-central Mexico. This river boosted the development of La Comarca Lagunera, a region of great economic importance to the country. However, regional development has led to the deterioration of this vital socio-ecosystem and its services. Despite these efforts, no studies have integrated multiple indicators to comprehensively assess the overall health of the basin. Instead, previous research has largely relied on isolated indicators. For this reason, this study prioritized an initial health assessment of the Nazas River, considering three main indicators: a biological indicator based on the fish community, a physicochemical indicator of water quality, and a physical indicator of the condition of the territory surrounding the river. The study found a marked gradient in overall health, ranging from the least degraded in the upper reaches (0.76 Ramos River and 0.68 Sextín River) of the river to the most degraded in the lower reaches (0.63 Lower Nazas), and highlighted the Peñón Blanco River in the middle section as a priority area for conservation and a possible biodiversity refuge due the Comprehensive Health Assessment 0.80.