Aquifers are one of the largest available freshwater resources. In this paper, total dissolved solids (TDS) of the groundwater aquifer in Tabriz plain is estimated by groundwater physicochemical parameters including Na, HCO3, Ca, Mg, and SO4 in the eastern region of Urmia Lake. For this purpose, four soft computing approaches, namely, multilayer perceptron (MLP), adaptive neuro-fuzzy inference system (ANFIS), support vector machine (SVM), and gene expression programming (GEP) were used to predict TDS for a period of ten years (2002–2012). Data were collected from the East Azerbaijan Regional Water Organization, which totaled 1,742 samples. In the application, of the whole data set, 70% (1,220 samples) was used for training and 30% (522 samples) for testing. In the following, the correlation coefficient (R), root mean square error (RMSE), and mean absolute error (MAE) statistics were used for evaluating the accuracy of the models. According to the results, MLP, ANFIS, SVM, and GEP models could be employed successfully in estimating TDS alterations. A comparison was made between these soft computing approaches that corroborated the superiority of the GEP model over MLP, SVM, and ANFIS models with RMSE = 58.93, R = 0.998, and MAE = 5.21.