BackgroundOxidative stress induced by free radical accumulation contributes to many pathologies, including cancer. Antioxidant defense system fails to scavenge free radicals when it is excessively accumulated. Assessing individual antioxidant enzymes and total antioxidant capacity could direct the customized therapeutic strategies.ObjectiveEvaluation of total antioxidant status and enzyme glutathione peroxidase activity in the oral cancer group compared to the healthy control group.MethodThe literature search included databases PubMed, Science Direct, Wiley Online Library, Cochrane and Cross Reference between 1999 and 2021. The database search was completed in the month of August 2022. The extracted data were analyzed by Comprehensive Meta‐Analysis (CMA) version 3 software (Biostat Inc. Englewood, NJ). Based on search strategies, 1435 articles have been retrieved from the database. In the segregated articles, 1365 were excluded due to duplicated articles, animal studies, low‐quality studies, articles unrelated to the research question, and with unmatched objectives. Based on inclusion criteria, 70 articles were selected for full‐text valuation. However, 33 articles were found highly suitable for inclusion and data extraction. Finally, 11 articles were selected for meta‐analysis.ResultsThe meta‐analysis of four included studies of tissue samples showed a significantly (p < .001) increased GPx activity in the oral cancer group, when compared to the control group, whereas three included studies of erythrocyte samples displayed a significantly (p < .001) decreased GPx activity in the oral cancer group than the control group with the pooled standardized mean difference value of −2.766 moles/min/g Hb at 95% CI (−3.297 to −2.234). The meta‐analysis of the included studies depicted an insignificant (p = .947) reduction of salivary TAS levels in the oral cancer group when compared to the control group.ConclusionOur systematic review and meta‐analysis depict antioxidant GPx enzyme activity in the regional tissue samples of the oral cancer group differs from other systemic biological fluid samples compared to the healthy control group.