Drinking water treatment plants (DWTPs) face changes in raw water quality, which affect the formation of disinfection by-products. Several empirical modelling approaches have been reported in the literature, but most of them have been developed with lab-scale data, which may not be representative of real water systems. Therefore, the application of these models for real-time operation of DWTPs might be limited. At the present study, multiple linear regression (MLR) and multi-layer perceptrons (MLP) were benchmarked using field-scale data for predicting the THMs formation in a case-study DWTP in Barcelona, Spain. After fitting the studied models, MLR exhibited good fit with the validation data set (R2 = 0.88 and MAE = 4.0 μg·L−1) and described the most plausible input-output relationships with field-scale data. The MLR predictive model was incorporated into an environmental decision support system (EDSS) for assessing the THMs formation at two critical points of the distribution network. A Monte Carlo scheme was applied for quantifying uncertainty of model predictions at these points, considering low and high water quality scenarios and different degrees of treatment by an electrodialysis reversal process. The results show that the use of the proposed EDSS can help in real operation of complex drinking water systems, which face important changes in water quality throughout the year.