<p>Peripheral nerve injury (PNI) is a major cause of disability, resulting in significant sensorimotor deficits and functional impairment. The amniotic membrane (AM), a natural semi-permeable polymeric material derived from living tissues, is rich in extracellular matrix components, growth factors, and other bioactive molecules. Celecoxib, a COX-2 inhibitor, has been proven to mitigate peripheral neuroinflammation. Although a nanofibrous polycaprolactone (PCL)-AM loaded with 8% celecoxib has previously been shown to prevent tendon adhesion, its potential role in PNI remains unexplored. In this study, a multilayer multifunctional nanofibrous composite membrane composed of PCL and AM incorporated with 8% celecoxib was fabricated via electrospinning. In vitro assays confirmed that the PCL-AM-8% celecoxib composite facilitated Schwann cell differentiation. Furthermore, this composite was wrapped around the repair site of the sciatic nerve in a rat model of sciatic nerve transection. Functionally, the PCL-AM-8% celecoxib composite reduced neuroinflammation and mitigated damage to the gastrocnemius muscle, as indicated by suppressed secretion of pro-inflammatory cytokines and decreased gastrocnemius fibrosis. Moreover, the composite ameliorated pathological injury in the sciatic nerve, promoted the expression of neurofilament protein NF-200 and the Schwann cell marker S100, enhanced Schwann cell differentiation, and thereby accelerated nerve regeneration and functional recovery. Mechanistic investigations revealed that the composite activated the PI3K-AKT signaling pathway. Collectively, these data demonstrate the promising therapeutic potential of the PCL-AM-8% celecoxib composite for the treatment of PNI and propose a novel strategy for its prevention and management.</p>