Water contamination is indeed a worldwide problem that threatens public health, environmental protection, and agricultural productivity. The distinctive attributes of machine learning (ML)-based modelling can provide in-depth understanding into increasing water quality challenges. This study presents the development of a multi-expression programming (MEP) based predictive model for water quality parameters, i.e., electrical conductivity (EC) and total dissolved solids (TDS) in the upper Indus River at two different outlet locations using 360 readings collected on a monthly basis. The optimized MEP models were assessed using different statistical measurements i.e., coefficient-of-determination (R2 ), root-mean-square error (RMSE), mean-absolute error (MAE), root-mean-square-logarithmic error (RMSLE) and mean-absolute-percent error (MAPE). The results show that the R2 in the testing phase (subjected to unseen data) for EC-MEP and TDS-MEP models is above 0.90, i.e., 0.9674 and 0.9725, respectively, reflecting the higher accuracy and generalized performance. Also, the error measures are quite lower. In accordance with MAPE statistics, both the MEP models shows an “excellent” performance in all three stages. In comparison with traditional non-linear regression models (NLRMs), the developed machine learning models have good generalization capabilities. The sensitivity analysis of the developed MEP models with regard to the significance of each input on the forecasted water quality parameters suggests that Cl and HCO3 have substantial impacts on the predictions of MEP models (EC and TDS), with a sensitiveness index above 0.90, although the influence of the Na is the less prominent. The results of this research suggest that the development of intelligence models for EC and TDS are cost effective and viable for the evaluation and monitoring of the quality of river water.