Background: – Critical-sized peripheral nerve defects remain a major reconstructive challenge. Although autografts are considered the gold standard, their use is limited by donor-site morbidity and graft availability. Acellular nerve allografts (ANAs) offer a promising alternative but are often hampered by inadequate revascularization and limited functional outcomes in large defects. This study investigates whether combining mesenchymal stem cell-derived secretome therapy with surgical angiogenesis can enhance the regenerative capacity of ANAs. Methods: – Forty male Wistar rats were randomly assigned to 5 groups (n=8): group 1 (reversed autograft), group 2 (ANA), group 3 (ANA+secretome), group 4 (ANA+surgical angiogenesis), and group 5 (ANA+secretome+surgical angiogenesis). A 10 mm sciatic nerve defect was created in all animals. Functional recovery was evaluated using the Sciatic Functional Index (SFI) at 6 and 9 weeks. Electrophysiological, histologic, immunohistochemical (CD34), and muscle weight/volume assessments were performed at 9 weeks. Results: – Group 5 demonstrated the highest functional recovery among ANA-based interventions, achieving outcomes comparable to autografts. Groups 4 and 5 showed significantly improved axonal regeneration compared with ANA alone. CD34 immunostaining revealed enhanced vascularization in groups 4 and 5, with levels similar to the autograft group. No significant differences were observed in electrophysiological or muscle mass parameters. Conclusions: – The combination of secretome therapy and surgical angiogenesis synergistically enhances the regenerative performance of acellular nerve allografts. This strategy may provide a clinically translatable alternative to autografts, particularly in challenging repair scenarios involving avascular or scarred recipient beds.