The selection of sites for permanent environmental monitoring of natural water bodies should rely on corresponding source apportionment studies. Tools like the water quality index (WQI) assessment may support this objective. This study aims to analyze a decade-long dataset of measurements of 26 chemical components at 26 observation points within the Irtysh River Basin, aiming to identify priority zones for stricter environmental regulations. It was achieved through the WQI tool integrated with geoinformation systems (GISs) and multivariate statistical techniques. The findings highlighted that both upstream sections of tributaries (Oba and Bukhtarma rivers) and the mainstream of the basin are generally in good condition, with slight fluctuations observed during flooding periods. Areas in the basin experiencing significant impacts from mining and domestic wastewater treatment activities were identified. The rivers Glubochanka (GL) and Krasnoyarka (KR) consistently experienced marginal water quality throughout the observation period. Various contaminant sources were found to influence water quality. The impact of domestic wastewater treatment facilities was represented by twofold elevated concentrations of chemical oxygen demand, reaching 22.6 and 27.1 mg/L for the KR and GL rivers, respectively. Natural factors were indicated by consistent slight exceedings of recommended calcium levels at the KR and GL rivers. These exceedances were most pronounced during the cold seasons, with an average value equal to 96 mg/L. Mining operations introduced extremal concentrations of trace elements like copper, reaching 0.046–0.051 mg/L, which is higher than the threshold by 12–13 times; zinc, which peaked at 1.57–2.96 mg/L, exceeding the set limit by almost 50–100 times; and cadmium, peaking at levels surpassing 1000 times the safe limit, reaching 0.8 mg/L. The adverse impact of mining activities was evident in the Tikhaya, Ulba, and Breksa rivers, showing similar trends in trace element concentrations. Seasonal effects were also investigated. Ice cover formation during cold seasons led to oxygen depletion and the exclusion of pollutants into the stream when ice melted, worsening water quality. Conversely, flooding events led to contaminant dilution, partially improving the WQI during flood seasons. Principal component analysis and hierarchical cluster analysis indicated that local natural processes, mining activities, and domestic wastewater discharge were the predominant influences on water quality within the study area. These findings can serve as a basis for enhanced environmental regulation in light of updated ecological legislation in Kazakhstan, advocating for the establishment of a comprehensive monitoring network and the reinforcement of requirements governing contaminating activities.