INTRODUCTION: Fluorosis, a condition resulting from excessive fluoride intake, leads to dental, skeletal, and soft tissue alterations through mechanisms that induce oxidative stress. With its potential to significantly impact the field, this review aims to assess the efficacy of antioxidant agents in murine models exhibiting fluorosis-induced toxicity. By transferring electrons to oxidizing agents, antioxidants can attenuate oxidation reactions and mitigate cellular damage. METHODOLOGY: This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, encompassing articles investigating the impact of antioxidant substances on murine fluorosis models, explicitly focusing on oxidative stress markers and antioxidant levels across various tissues. RESULTS: A qualitative synthesis of 79 articles highlights antioxidant agents such as vitamin C, vitamin E, selenium, carotenoids, polyphenolic compounds (including flavonoids and polyphenolic acids), amino acids, and others among animals with fluorosis induction showed variations in oxidative stress markers and antioxidant activity levels under different administration protocols compared to those receiving prophylactic, concomitant concurrent, or therapeutic antioxidant treatments. CONCLUSION: Fluoride administration across diverse doses and durations elicits heightened oxidative stress markers in multiple rodent tissues. The current evidence suggests that some antioxidants are effective as a prophylactic and concurrent in murine models of fluorosis. However, the methodological differences between studies prevent the establishment of a protocol for potential standardized use.