Water is a vital yet limited resource, increasingly threatened in both availability and quality as the global population continues to grow. Amid rapid urbanization and industrialization, assessing and predicting drinking water quality presents significant challenges due to the diversity of pollution sources and the complexity of temporal variations. The objective of the current study is to determine the concentration of physiochemical parameters in surface water intended for drinking, together with any potential dangers to human health, and to identify any substantial anthropogenic pressures in the Mahanadi River in Odisha. Monitoring and evaluating often is necessary to maintain the good status of the water quality (WQ). The water quality index (WQI) model is one of the most used methods for evaluating the quality of water. Further, the basis for the water quality evaluation program is in line with Canadian Council of Ministers of the Environment water quality index (CCME-WQI), water pollution index (WPI), and contamination index (CI) analysis, employing computed excursions, during the estimation of WQI values. For the purpose of this research, samples of water were gathered from nineteen locations, during monsoon season (June–September), encompassing both urbanized and non-urbanized parts during 2022–2023, and its acquired specimens were analyzed for twenty usual WQ variables. It is noticed that most of the WQ indicators were behind the guideline value of the World Health Organization (WHO) for surface water except TKN and coliform. It is predominantly found in the overall region that all water samples show mild-alkaline behavior. The TKN content is discovered to be inversely correlated with the presence of nitrogen fertilizer and shell debris, whereas the coliform is produced from inflow from rivers and the coast, that serves as a principal contributor. The CCME-WQI result displayed that the quality of water is found to be “good” to “poor” quality, and rest 10.53% water is only viable under specific circumstances for specific goals. Further, on the basis of WPI and CI, the physicochemical state of the river, i.e., 63.16% of samples, was referred to as “good,” and therefore rest 36.84% of locations requires monitoring for ecosystem sustainability. The findings of this ongoing research highlight that urban pressures, parent rock weathering, and urban-industrial activities significantly influence river water quality. To mitigate effluents from surrounding agricultural and industrial sources, continuous monitoring and strategic guidance are essential. However, by integrating the employed methodologies, their individual strengths are preserved, and valuable insights into water management are uncovered, that shedding light on the underlying factors affecting water quality in different types of surface water bodies. Ultimately, this study contributes to preserving the river’s diverse ecosystem and ensuring the provision of high-quality water to support sustainable urban development.