ObjectiveA feared complication of aminoglycoside treatment is ototoxicity, which is theorized to be attributed to the production of aminoglycoside‐induced reactive oxygen species. Previous studies using animal models have suggested that numerous therapies targeting reducing oxidative stress may prevent ototoxicity from aminoglycosides. However, few clinical studies have been conducted on these antioxidants. This systematic review and meta‐analysis examines the effectiveness of antioxidant therapies in the treatment of aminoglycoside‐induced ototoxicity.Data SourcesPubMed, Embase, Web of Science, and ClinicalTrials.gov.Review MethodA literature search was conducted in August 2024. This review sought randomized controlled trials to be conducted on humans to examining otologic outcomes in aminoglycoside‐induced ototoxicity following administration of medications intended to reduce oxidative stress.ResultsA systematic review yielded 2037 results, of which seven studies met inclusion criteria. N‐acetylcysteine (NAC) was investigated in four studies, aspirin in two studies, and vitamin E in one study. Six studies examined the benefit of antioxidant treatments for up to 8 weeks after administration while one study tested subjects' hearing after 1 year. In pooled analysis, two studies assessing NAC showed the greatest reduction in ototoxicity (RR 0.112, 95% CI, 0.032–0.395; p = 0.0007; I2 = 18%), followed by two studies examining aspirin (RR 0.229, 95% CI, 0.080–0.650; p = 0.0057; I2 = 0%). One study performed with vitamin E did not find a reduction in ototoxicity compared to the placebo (RR 0.841, 95% CI, 0.153–4.617; p = 0.8416).ConclusionsMultiple studies have shown that NAC and aspirin are effective in reducing ototoxicity from treatment with aminoglycosides. However, there is a lack of high‐quality evidence. Additional studies should examine whether aspirin and N‐acetylcysteine provide long‐term benefit, and which of the other promising antioxidants translate from animal models.Level of EvidenceN/A Laryngoscope, 2024