Objective: Radiation therapy is commonplace for cancer treatment but often results in fibrosis and atrophy of surrounding soft tissue. Decellularized adipose matrices (DAMs) have been reported to improve these soft tissue defects through the promotion of adipogenesis. These matrices are decellularized by a combination of physical, chemical, and enzymatic methods to minimize their immunologic effects while promoting their regenerative effects. In this study, we aimed at exploring the regenerative ability of a DAM (renuva®; MTF biologics, Edison, NJ) in radiation-induced soft tissue injury. Approach: Fresh human lipoaspirate or DAM was injected into the irradiated scalp of CD-1 nude mice, and volume retention was monitored radiographically over 8 weeks. Explanted grafts were histologically assessed, and overlying skin was examined histologically and biomechanically. Irradiated human skin was also evaluated from patients after fat grafting or DAM injection. However, integrating data between murine and human skin in all cohorts is limited given the genetic variability between the two species. Results: Volume retention was found to be greater with fat grafts, though DAM retention was, nonetheless, appreciated at irradiated sites. Improvement in both mouse and human irradiated skin overlying fat and DAM grafts was observed in terms of biomechanical stiffness, dermal thickness, collagen density, collagen fiber networks, and skin vascularity. Innovation: This is the first demonstration of the use of DAMs for augmenting the regenerative potential of irradiated mouse and human skin. Conclusions: These findings support the use of DAMs to address soft tissue atrophy after radiation therapy. Morphological characteristics of the irradiated skin can also be improved with DAM grafting.