The present study aimed to assess the impact of anthropogenic stressors on the physico-chemical characteristics and water quality of the River Ganga employing a GIS-based approach in the middle Gangetic Plain at Patna, India. After the survey, sand mining, bridge construction, and disposal of untreated domestic and sewage wastes were selected as major anthropogenic stressors. A total of 48 samples were collected in pre-monsoon and post-monsoon seasons of 2022 and were analyzed for 16 physico-chemical parameters, namely WT (water temperature), pH, EC (electrical conductivity), TDS, turbidity, DO (dissolved oxygen), BOD (biological oxygen demand), TH (total hardness), Ca2+, Mg2+, Na+, K+, Cl−, and SO4− ions, respectively, in accordance with standard protocol. The WQI was calculated using the Weighted Arithmetic Water Quality Index (WAQWI) method and spatial maps were created using ArcGIS software. The result revealed significant seasonal variation in several physico- chemical parameters except for Ca2+, K+ and TA (p > 0.05). ANOVA revealed significant variation for BOD and COD at Ghagha and Triveni, whereas for nitrate at Gai Ghat reference and impact sites, respectively. The Water Quality Index (WQI) revealed a deterioration in water quality by 60% in post-monsoon season. HCA revealed that the WQI was mostly governed by TDS, TH, TA, and EC.