The design of a water quality monitoring network (WQMN) is a complicated decision-making process because each sampling involves high installation, operational, and maintenance costs. Therefore, data with the highest information content should be collected. The effect of seasonal variation in point and diffuse pollution loadings on river water quality may have a significant impact on the optimal selection of sampling locations, but this possible effect has never been addressed in the evaluation and design of monitoring networks. The present study proposes a systematic approach for siting an optimal number and location of river water quality sampling stations based on seasonal or monsoonal variations in both point and diffuse pollution loadings. The proposed approach conceptualizes water quality monitoring as a two-stage process; the first stage of which is to consider all potential water quality sampling sites, selected based on the existing guidelines or frameworks, and the locations of both point and diffuse pollution sources. The monitoring at all sampling sites thus identified should be continued for an adequate period of time to account for the effect of the monsoon season. In the second stage, the monitoring network is then designed separately for monsoon and non-monsoon periods by optimizing the number and locations of sampling sites, using a modified Sanders approach. The impacts of human interventions on the design of the sampling net are quantified geospatially by estimating diffuse pollution loads and verified with land use map. To demonstrate the proposed methodology, the Kali River basin in the western Uttar Pradesh state of India was selected as a study area. The final design suggests consequential pre- and post-monsoonal changes in the location and priority of water quality monitoring stations based on the seasonal variation of point and diffuse pollution loadings.