The biomechanical and metabolic demands of human running are distinctly affected by velocity and body weight. As runners increase velocity, ground reaction forces (GRF) increase, which may increase the risk of an overuse injury, and more metabolic power is required to produce greater rates of muscular force generation. Running with weight support attenuates GRFs, but demands less metabolic power than normal weight running. We used a recently developed device (G-trainer) that uses positive air pressure around the lower body to support body weight during treadmill running. Our scientific goal was to quantify the separate and combined effects of running velocity and weight support on GRFs and metabolic power. After obtaining this basic data set, we identified velocity and weight support combinations that resulted in different peak GRFs, yet demanded the same metabolic power. Ideal combinations of velocity and weight could potentially reduce biomechanical risks by attenuating peak GRFs while maintaining aerobic and neuromuscular benefits. Indeed, we found many combinations that decreased peak vertical GRFs yet demanded the same metabolic power as running slower at normal weight. This approach of manipulating velocity and weight during running may prove effective as a training and/or rehabilitation strategy.