Numerical models are important tools for analyzing and solving water resources problems; however, a model’s reliability heavily depends on its calibration. This paper presents a method based on Design of Experiments theory for calibrating numerical models of rivers by considering the interaction between different calibration parameters, identifying the most sensitive parameters and finding a value or a range of values for which the calibration parameters produces an adequate performance of the model in terms of accuracy. The method consists of a systematic process for assessing the qualitative and quantitative performance of a hydromorphological numeric model. A 75 km reach of the Meta River, in Colombia, was used as case study for validating the method. The modeling was conducted by using the software package MIKE-21C, a two-dimensional flow model. The calibration is assessed by means of an Overall Weighted Indicator, based on the coefficient of determination of the calibration parameters and within a range from 0 to 1. For the case study, the most significant calibration parameters were the sediment transport equation, the riverbed load factor and the suspended load factor. The optimal calibration produced an Overall Weighted Indicator equal to 0.857. The method can be applied to any type of morphological models.