The economic development, livelihood and drinking water of millions of people in the central plateau of Iran depend on the Qarah-Chay River, but due to a lack of inappropriate monitoring, it has been exposed to destruction and pollution. Consequently, an assessment of the river’s water quality is of utmost importance for both the management of human health and the maintenance of a safe environment, which can be achieved by determining the best locations for pollution monitoring stations along rivers. In this study, artificial neural networks (ANNs) has been used to optimize the locations for Qarah-Chay River monitoring stations in Markazi province, Iran. The data are collected based on the Iranian Water Quality Index (IRWQI), the US National Sanitation Foundation Water Quality Index (NSFWQI) and the Oregon Water Quality Index (OWQI). The database is given to a multilayer perceptron (MLP) neural network along with a geographic information system (GIS). The output of this study identified six pollution monitoring stations on the river, which are mainly downstream due to the accumulation of land uses and the concentration of pollution. The gradient of the MLP network training courses model from the proposed monitoring stations is 0.062299. In addition, the performance evaluation criteria of the proposed MLP model for F1-score, recall, precision and accuracy were 0.85, 0.84, 0.88 and 0.88, respectively. The results obtained help managers to properly monitor the river’s water resources with accuracy, efficiency and lower cost; furthermore, the findings were able to provide scientific references for river water quality monitoring and river ecosystem protection.