To compare the outcomes between idebenone oral therapy and rAAV2-ND4 intravitreal injection in the treatment of Leber’s hereditary optic neuropathy. A systematic literature review was performed of publications from 1990 to 2023 in PubMed, Ovid MEDLINE, Cochrane CENTRAL, Google Scholar, Embase, CrossRef, OpenAlex, and Web of Science for studies evaluating the outcomes of idebenone or rAAV2-ND4 therapy in Leber’s hereditary optic neuropathy. The primary outcome measure was improvement in visual acuity. Secondary outcome measures were improvement of retinal nerve fiber layer thickness, ganglion cell layer volume, and visual field mean deviation. There are no studies directly comparing the two interventions. Our analysis included 645 patients from 17 studies; 338 patients from nine studies received idebenone, and 307 patients from eight studies received rAAV2-ND4. When compared to each other, rAAV2-ND4 provided better visual improvement at 6 months with a mean difference of 0.07 (P = 0.8289), but idebenone provided better visual improvement at 1 year with a mean difference of 0.35 (P < 0.0001). At 2 years, the rAAV2-ND4 group’s visual acuity improved from baseline by 0.18 (P = 0.08). There was no data for improvement at 2 years for idebenone, only for rAAV2-ND4. rAAV2-ND4 provides better visual acuity results at 6 months, and idebenone provides better visual acuity results at 1 year. Further studies are recommended to formulate a complete idea about the long-term results (>2 years).