In this study, an experimental system entailing ciprofloxacin hydrochloride (CIP) removal from aqueous solution is modeled by using artificial neural networks (ANNs). For modeling of CIP removal from aqueous solution using bentonite and activated carbon, we utilized the combination of output-dependent data scaling (ODDS) with ANN, and the combination of ODDS with multivariable linear regression model (MVLR). The ANN model normalized via ODDS performs better in comparison with the ANN model scaled via standard normalization. Four distinct hybrid models, ANN with standard normalization, ANN with ODDS, MVLR with standard normalization, and MVLR with ODDS, were also applied. We observed that ANN and MVLR estimations’ consistency, accuracy ratios and model performances increase as a result of pre-processing with ODDS.