Purpose <p>Spinal cord injury (SCI) is a devastating condition with limited therapeutic options owing to poor intrinsic regeneration and the formation of glial scars. Platelet-rich plasma (PRP)-based biomaterials have emerged as promising candidates for neural repair; however, their application in complete SCI models with rigorous multimodal validation has not yet been investigated. This study aimed to extend the current knowledge on SCI-PRP based study,&#xa0;by developing and comprehensively validating a clinically translatable PRP-derived fibrin scaffold for spinal cord regeneration.</p> Methods <p>PRP-fibrin scaffolds were synthesized from donor-derived plasma and extensively characterized in terms of their physicochemical properties, degradation profiles, protein release dynamics, and cellular compatibility. Its regenerative potential was evaluated using an integrative pipeline that included <i>in ovo</i> chorioallantoic membrane (CAM) assays, a complete spinal cord transection rat model, and multimodal outcome measures, including magnetic resonance imaging (MRI), retrograde neuronal tract&#xa0;tracing, electrophysiological recordings, and gene expression analyses.</p> Results <p>The scaffold exhibited favorable structural and biochemical characteristics, supported angiogenesis in the CAM assay, and promoted tissue integration <i>in vivo</i>. In an SCI model, the scaffold significantly enhanced neovascularization, reduced glial scarring, and facilitated axonal regeneration. Functional improvements were observed 30&#xa0;days’ post-implantation. <i>In silico</i> docking further demonstrated stable interactions between scaffold proteins and key neuroregenerative signaling molecules.</p> Conclusion <p>This study provides multimodal validation of the derived fibrin scaffold, establishing it as a robust ECM-mimetic platform for spinal cord repair. These findings lay the groundwork for future clinical translation of SCI therapeutics.</p> Graphical Abstract <p></p>