PURPOSE: This review aims to systematically review the available evidence on neuroprotective agents for optic neuritis, evaluating their effectiveness and safety. METHODS: This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. To collect the studies, we searched electronic databases including MEDLINE, Cochrane Library, and EMBASE in May 2023. A pre-established protocol of the systemic review was registered in the International Prospective Register of Systematic Reviews, ID Number: (CRD42023448479). RESULTS: Regarding the global loss of RNFL, a statistical significance was observed in favor of erythropoietin compared to placebo (MD = - 5.40, 95%CI, - 7.27-- 3.53). The overall difference in VEP latency recovery was insignificant (MD = - 0.63, 95%CI, - 5.95-4.69). The distinctness in visual acuity measured in logMAR in the memantine group was significant (MD = - 0.25, 95%CI, - 0.33-- 0.16). Two of the included studies had no major adverse events, however, the likelihood of major adverse events was significant overall in the other studies (RR = 2.28, 95%CI, 1.16 to 4.47). The erythropoietin group had 12 cases of major adverse events with a RR = 2.35. CONCLUSION: Evaluating neuroprotective agents for ON produced mixed findings. Although erythropoietin was effective in reducing the thinning of RNFL, it did not lead to improved visual acuity results. On the other hand, our analysis found that memantine significantly improved VA compared to placebo. Notably, the experimental groups had more frequent adverse events, particularly with erythropoietin. Thus, caution is advised when contemplating the use of these agents.