<p>Objective: Moderate-to-severe pain is common after spine surgery. While opioids remain standard analgesia, their adverse effects have prompted opioid-sparing strategies. This systematic review evaluates the safety and efficacy of nefopam, a non-opioid and non-NSAID, as adjuvant perioperative analgesia in spine surgery. Methods: Medline, Embase, Scopus and Cochrane databases were searched from inception to May 9, 2025. RevMan V5.4 was used to analyse mean differences (MD) or standardised mean differences (SMD) and 95% confidence intervals (CIs) for continuous outcomes and risk ratios (RR) with 95% CIs for dichotomous outcomes. The GRADE framework was used to assess the certainty of evidence. Results: Seven randomised controlled trials (n = 553) were included. Nefopam did not reduce 24-hour morphine use (MD -1.47 mg; 95% CI: -3.86 to 0.92 mg; GRADE moderate), 24-hour incisional pain (SMD, -0.01; 95% CI -0.22 to 0.20; GRADE moderate), 48-hour incisional pain (SMD, -0.24; 95% CI -0.50 to 0.02; GRADE low), 24-hour neuropathic pain (SMD, -0.19; 95% CI -0.49 to 0.10; GRADE low), 72-hour neuropathic pain (SMD, -0.33; 95% CI -1.02 to 0.36; GRADE very low), or length of stay (MD, 0.08days; 95% CI -0.73 to 0.88days; GRADE Low). There were no significant differences in drug-related adverse effects (sedation (RR 1.30), nausea/vomiting (RR 1.03), dizziness (RR 1.14), and urinary retention (RR 2.36)), (GRADE: very low to low). Conclusion: Perioperative nefopam did not reduce acute morphine use, pain scores, hospital stay, or drug-related adverse events in spine surgery, though most studies used doses below the median effective dose, limiting conclusions on its efficacy and safety.</p>