Connecting the legs with a spring attached to the shoelaces, called an exotendon, can reduce the energetic cost of running, but how the exotendon reduces the energetic burden of individual muscles remains unknown. We generated muscle-driven simulations of seven individuals running with and without the exotendon to discern whether savings occurred during the stance phase or the swing phase, and to identify which muscles contributed to energy savings. We computed differences in muscle-level energy consumption, muscle activations, and changes in muscle-fiber velocity and force between running with and without the exotendon. The seven of nine participants who reduced energy cost when running with the exotendon reduced their measured energy expenditure rate by 0.9 W/kg (8.3%). Simulations predicted a 1.4 W/kg (12.0%) reduction in the average rate of energy expenditure and correctly identified that the exotendon reduced rates of energy expenditure for all seven individuals. Simulations showed most of the savings occurred during stance (1.5 W/kg), though the rate of energy expenditure was also reduced during swing (0.3 W/kg). The energetic savings were distributed across the quadriceps, hip flexor, hip abductor, hamstring, hip adductor, and hip extensor muscle groups, whereas no changes were observed in the plantarflexor or dorsiflexor muscles. Energetic savings were facilitated by reductions in the rate of mechanical work performed by muscles and their estimated rate of heat production. By modeling muscle-level energetics, this simulation framework accurately captured measured changes in whole-body energetics when using an assistive device. This is a useful first step towards using simulation to accelerate device design by predicting how humans will interact with assistive devices that have yet to be built.