This dissertation investigates how aging alters the biological, molecular, and structural processes that guide skeletal muscle regeneration and evaluates how these age-related changes impact the effectiveness of emerging tissue-engineered therapies. Using in vitro engineered matrices, in vivo volumetric muscle loss models, and a combined regenerative rehabilitation approach, this work identifies age-dependent barriers to myogenesis, functional recovery, and therapeutic response. Together, these studies provide mechanistic insight to support the design of biomaterial-based interventions that are effective for all ages.