A mathematical model of whole-body metabolism is developed to predict glucose homeostasis during exercise by using a hormonal controller over cellular metabolic processes. Model simulations were validated with experimental data from exercise studies in humans. The exercise-induced changes in hormonal signals modulated metabolic flux rates of various tissues in a coordinated way to maintain blood glucose constant. This study demonstrates the efficacy of a multi-tissue controller to accomplish blood glucose homeostasis by integrating the outputs of tissues under hormonal control. In conclusion, this model can be used as a valuable complement to experimental studies due to its ability to predict what is difficult to measure directly and to provide dynamic information about the system.