Study design <p>Systematic Review</p> Objectives <p>To systematically examine the use of bioengineered scaffolds, with/without bioactive agents, drugs, or cellular transplants in preclinical animal models and human studies of spinal cord injury (SCI).</p> Setting <p>Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences</p> Methods <p>A systematic review and meta-analysis was conducted following PRISMA guidelines and registered in PROSPERO (ID: CRD42023437266). A comprehensive search in MEDLINE and Embase on 8/27/2023 identified studies on scaffolds as neuroregenerative and neuroprotective treatments for SCI. Human studies were assessed using ROBINS-I, and meta-analysis focused on clinical outcomes.</p> Results <p>Of 4561 articles screened, 931 studies were included: in-vivo (82%), in-vitro (16%), and human studies (1%). Various biomaterials (<i>N</i> = 82; natural: 38%; synthetic: 62%), cell types (<i>N</i> = 27; NSCs: 24%, Schwann cells: 13%, NPCs: 12%), bioactive agents (<i>N</i> = 38; NT-3: 32%, BDNF: 25%, FGF: 24%), and pharmacological agents (<i>N</i> = 88; chABC: 12%, heparin: 11%, taxels: 10%) were analyzed. Fourteen human studies included acute and chronic SCI patients, with cervical (36%) and thoracic SCI (64%). Clinical trials demonstrated moderate to low quality (ROBINS-I). Our meta-analysis indicated that the pooled 2-scale AIS conversion rate was 30.59% (<i>p</i> = 0.005) ranging from 33.46% (<i>p</i> = 0.036) in acute to 28.35% (<i>p</i> = 0.084) in chronic SCI. Furthermore, the pooled 1-scale AIS conversion rate was 11.79% (<i>p</i> = 0.011), spanning from 17.31% (<i>p</i> = 0.131) in acute to 7.44% (<i>p</i> = 0.081) in chronic SCI.</p> Conclusion <p>Scaffold implantation shows promising neuroregenerative potential, evidenced by AIS grade improvement in human studies. Scaffolds are advancing rapidly from laboratory research to clinical trials, expanding treatment options for SCI.</p>