Applying complex mathematical models of physiological systems is challenging due to the large number of parameters. Identifying these parameters through experimentation is difficult, and although procedures for fitting and validating models are reported, no integrated strategy exists. Additionally, the complexity of optimization is generally neglected when the number of experimental observations is restricted, obtaining multiple solutions or results without physiological justification. This work proposes a fitting and validation strategy for physiological models with many parameters under various populations, stimuli, and experimental conditions. A cardiorespiratory system model is used as a case study, and the strategy, model, computational implementation, and data analysis are described. Using optimized parameter values, model simulations are compared to those obtained using nominal values, with experimental data as a reference. Overall, a reduction in prediction error is achieved compared to that reported for model building. Furthermore, the behavior and accuracy of all the predictions in the steady state were improved. The results validate the fitted model and provide evidence of the proposed strategy’s usefulness.