Skeletal muscle stem cells (MuSCs) are required for quick and effective muscle repair, making MuSCs promising therapeutic targets for tissue engineering and regenerative medicine. The environment MuSCs live in impacts their behavior. Muscles push and pull, giving mechanical cues to MuSCs, however how these mechanical cues affect how well MuSCs can rebuild tissues is unknown. We created a hydrogel that can be softened or stiffened on demand. Soft hydrogels, mimicking healthy muscle promote MuSC activation and expansion, while stiff hydrogels impair MuSC proliferation and arrest myogenic progression. Different structural and soluble cellular factors present in the MuSC environment can exacerbate or mitigate this effect. The cellular response to a stiff microenvironment is fixed within the first three days of culture, as subsequent softening back to a healthy stiffness did not rescue MuSC proliferation or myogenic progression. These results highlight the importance of temporally controlled biophysical and biochemical cues in regulating MuSC fate that can be harnessed to improve regenerative medicine approaches to restore skeletal muscle tissue.