With human space exploration back in the spotlight, recent studies have investigated the neuromuscular adjustments to simulated hypogravity running. They have examined the activity of individual muscles, whereas the central nervous system may rather activate groups of functionally related muscles, known as muscle synergies. To understand how locomotor control adjusts to simulated hypogravity, we examined the temporal (motor primitives) and spatial (motor modules) components of muscle synergies in participants running sequentially at 100%, 60%, and 100% body weight on a treadmill. Our results highlighted the paradoxical nature of simulated hypogravity running: The reduced mechanical constraints allowed for a more flexible locomotor control, which correlated with the degree of spatiotemporal adjustments. Yet, the increased temporal (shortened stance phase) and sensory (deteriorated proprioceptive feedback) constraints required wider motor primitives and a higher contribution of the hamstring muscles during the stance phase. These results are a first step towards improving astronaut training protocols.