Oxaceprol, a derivative of l-proline, is an established drug for managing osteoarthritis (OA) with a better safety profile than non-steroidal anti-inflammatory drugs (NSAIDs). This systematic review and meta-analysis, following Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines, evaluated the efficacy, safety and tolerability of oxaceprol in OA. Electronic databases for published and grey (unpublished) literature were searched to identify parallel-group randomized controlled trials (RCTs) evaluating the impact of oxaceprol in patients with OA. The risk of bias was assessed using the Cochrane collaboration tool. A total of seven parallel-group RCTs involving 1087 participants were included in the systematic review. The meta-analysis, in review manager, demonstrated numerically greater/significant improvements compared to active control [diclofenac/ibuprofen]/placebo in pain and function of joint; similar improvement vs. active control in global treatment efficacy; no difference/significant difference vs. active control/placebo in NSAIDs as rescue medication. Treatment with oxaceprol showed numerically less adverse events (AEs) than active control (diclofenac: risk ratio [RR], 0.71; 95% confidence interval [CI], 0.45 to 1.11; p=0.14: ibuprofen: RR, 0.73; 95% CI, 0.30 to 1.78; p=0.49) and significantly fewer AEs compared to placebo (RR, 0.76; 95% CI, 0.63 to 0.92; p=0.004). Given the nature of small-to-moderate sample size and the short duration of eligible studies, the available clinical evidence of oxaceprol in the management of OA is modest – though looks promising. New and better RCTs with larger sample sizes and longer follow-up are warranted to strengthen the use of oxaceprol in a clinical setting for managing OA.