BACKGROUND: Perioperative oxidative stress plays a role in organ injury and pain and could be improved by the antioxidant effects of vitamin C. METHODS: We performed a systematic review and meta-analysis of RCTs comparing perioperative vitamin C administration vs placebo or no treatment in adults undergoing noncardiac surgery. The primary outcome was hospital length of stay (LOS). RESULTS: Thirty-seven RCTs and 2747 patients were included. Administration of vitamin C was associated with no difference in LOS (mean difference=0.02 day; 95% confidence interval [CI], -0.30 to 0.35; P=0.88). Mortality did not differ between groups (relative risk=1.04; 95% CI, 0.52 to 2.08; P=0.5). No trials reported on other major postoperative complications. Vitamin C was associated with a reduction in postoperative pain score and cumulative morphine consumption up to 48 h after surgery. The incidence of complex regional pain syndrome was lower in orthopaedic patients receiving vitamin C. Adverse events were present in three RCTs (n=157), absent in 10 RCTs (n=957), and not reported in 25 RCTs (n=1570). One trial (n=20) in kidney transplantation surgery was stopped early because of safety concerns on vitamin C. The quality of evidence ranged from moderate to very low. CONCLUSIONS: Administration of vitamin C was not associated with a decrease in LOS after noncardiac surgery. The effects on morbidity and mortality are inconclusive and mostly uninvestigated. A small reduction in postoperative pain was found. Adverse events were rare but not systematically assessed. The evidence is uncertain, not supporting the use of vitamin C outside an experimental setting. STUDY PROTOCOL: PROSPERO database, CRD42021241654.