The deterioration of superficial water quality is a significant concern in water management. Currently, most European rivers do not achieve qualitative standards defined by Directive 2000/60/EC (Water Framework Directive, WFD), while the health status of many surface water bodies remains unknown. Within this context, we propose a new methodology to perform a semi-quantitative analysis of the pressure state of a river, starting from easily accessible data related to anthropic activities. The proposed approach aims to address the endemic scarcity of monitoring records. This study proposes a procedure to (i) evaluate the relative pressure of different human activities, (ii) identify allocation points of different pollutant sources along the river using a raster-based approach, and (iii) determine a spatial biochemical water quality index. The developed index expresses the overall biochemical state of surface water induced by pollutant sources that may simultaneously impact a single river segment. This includes establishments under the so-called Seveso Directive, activities subjected to the IPPC-IED discipline, wastewater treatment plants, and contaminated sites. The methodology has been tested over three rivers in Northern Italy, each exposed to different industrial and anthropogenic pressures: Reno, Enza, and Parma. A comparison with monitored data yielded convincing results, proving the consistency of the proposed index in reproducing the spatial variability of the river water quality. While additional investigations are necessary, the developed methodology can serve as a valuable tool to support decision-making processes and predictive studies in areas lacking or having limited water quality monitoring data.