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An automatic calibration framework of water quality parameters for surface runoff during modeling with InfoWorks ICM was constructed. The framework is based on a genetic algorithm (GA) and fully considers the calibration sequence for multiple water pollutants, namely, total suspended solids (TSS), chemical oxygen demand (COD), total nitrogen (TN), and total phosphorous (TP). Meanwhile, four different objective functions including the Nash–Sutcliff efficiency coefficient (NSE), coefficient of determination (R2), percentage error in the peak (PEP), and percentage bias (PBIAS) were selected as fitness evaluators for the GA. The framework was applied successfully to a specific area of Fuzhou in China, and the multi-objective results were compared with the single-objective results. The comprehensive indexes of TSS, COD, TN, and TP by multi-objective calibration were lower than that of the single-objective calibration in both scenarios. Compared with single-objective calibration, the iterations to reach the optimal value were shortened 9, 5, 13, and 15 iterations by multi-objective calibration. Therefore, the findings showed that the multi-objective function GA was more balanced and more efficient than the single-objective function GA. Then, the uncertainty of the model was evaluated by using the samples generated by automatic calibration, which provided a reliable basis for the subsequent application of the model. This framework can be applied to other programs through adjustments of the number and weight of objective functions according to the specific situation, which will make the modeling more efficient and accurate. [ABSTRACT FROM AUTHOR]