Purpose: Demonstrate the utility of System Dynamics computer modeling to study and gain insight into the impacts of physical activity and diet on weight gain and loss. Methods: A holistic System Dynamics computer model is presented that integrates the processes of human metabolism, hormonal regulation, body composition, nutrition, and physical activity. These processes are not independent of one another, and the model captures the complex interdependencies between them in the regulation of body weight and energy metabolism. The article demonstrates how such an integrative simulation model can serve as a viable laboratory tool for controlled experimentation to investigate the impacts of physical activity and diet on body weight and composition. Results: In one experiment, weight loss from a moderate level of daily exercise was slightly less than the loss from dieting. Although exercise did have a favorable impact on body composition by protecting against the loss in fat-free mass (FFM), it, however, failed to blunt the drop in resting energy expenditure (REE) that accompanies diet-based weight loss. The smaller loss in FFM did indeed induce a smaller drop in nominal REE, however, the preservation of FFM also affected a relatively larger loss in FM, which, in turn, induced a larger adaptive reduction in the metabolic rate. The two adaptations almost totally offset one another, causing minimal differences in REE. In a second experiment, exercise regimens of moderate- to high-level intensity proved counterproductive as weight-reducing strategies. However, when the diet was changed from a balanced composition to one that was highly loaded with carbohydrates, it became possible to sustain the intense exercise regimen over the experimental period and achieve a significant drop in body weight. Conclusion: The results underscore the significant interaction effects between physical activity, diet, and body composition and demonstrate the utility of computer-based experimentation to study, gain insight into, and make predictions about their dynamics.