AbstractRecent developments in the field of regenerative surgeries and medical applications have led to a renewed interest in adipose tissue‐enriched mesenchymal stem cell scaffolds. Various advantages declared for the decellularized adipose matrix (DAM) have caused its extensive use in the transfer of stem cells or growth factors for soft tissue regeneration induction. Meanwhile, the long‐term application of detergents toward DAM regeneration has been assumed as a risky obstacle in this era. Herein, a rapid, mechanical protocol was developed to prepare DAM (M‐DAM) without chemicals/enzymes and was comprehensively compared with the ordinary DAM (traditional chemical method). Accordingly, this method could effectively hinder oils and cells, sustain the structural and biological elements, and contain a superior level of collagen content. In addition, more protein numbers, as well as higher basement membrane elements, glycoproteins, and extracellular matrix‐related proteins were detected in the regenerated M‐DAM. Also, superior adipogenesis and angiogenesis proteins were distinguished. The noncytotoxicity of the M‐DAM was also approved, and a natural ecological niche was observed for the proliferation and differentiation of stem cells, confirming its great potential for vascularization and adipogenesis in vivo. The suggested technique could effectively prepare the modified DAM in variant constructions of tablets, powders, emulsions, hydrogels, and different three‐dimensional‐printed structures. Hence, this rapid, mechanical process can produce bioactive DAM, which has the potential to be widely used in various research fields of regenerative medicine.