A crucial part in designing a robust water quality monitoring network is the selection of appropriate water quality sampling locations. Due to cost and time constraints, it is essential to identify and select these locations in an accurate and efficient manner. The main contribution of the present article is the development of a practical methodology for allocating critical sampling points in present and future conditions of the non-point sources under a case study of the Khoy watershed in northwest Iran, where financial resources and water quality data are limited. To achieve this purpose, the river mixing length method (RML) was applied to propose potential sampling points. A new non-point source potential pollution score (NPPS) was then proposed by the analytic network process (ANP) to classify the importance of each sampling point prior to selecting the most appropriate locations for a river system. In addition, an integrated cellular automata–Markov chain model (CA–Markov) was applied to simulate future change in non-point sources during the period 2026–2036. Finally, by considering anthropogenic activities through land-use mapping, the hierarchy value, the non-point source potential pollution score values and budget deficiency in the study area, the seven sampling points were identified for the present and the future. It is not expected, however, that the present location of the proposed sampling points will change in the future due to the forthcoming changes in non-point sources. The current study provides important insights into the design of a reliable water quality monitoring network with a high level of assurance under certain changes in non-point sources. Furthermore, the results of this study should be valuable for water quality monitoring agencies looking for a cost-effective approach for selecting sampling locations.