Background: Coenzyme Q10 (CoQ10) has been known as ubiquinone or ubidecarenone, which is a kind of lipid-soluble and vitamin-like antioxidant. It has a potent antioxidant effect against oxidation status via various mechanisms, including its ability to regenerate other antioxidants, such as vitamin E and vitamin C, and to increase antioxidant enzymes. Moreover, CoQ10 can quench free radicals and prevent lipid peroxidation. The aim of this systematic review and meta-analysis was to evaluate the effect of CoQ10 on oxidative stress variables. Methods: A comprehensive electronic database search in Scopus, Web of Science, Embase, Cochrane Library, and Medline was performed to identify eligible randomized clinical trials. A meta-analysis of included studies was performed on selected variables using a random-effects model. Quality assessment was conducted by means of the Cochrane risk of bias assessment tool. Results: To evaluate the effect of CoQ10 supplementation, 17 trials and 972 participants were included for the meta-analysis. The pooled analysis of primary studies showed that CoQ10 increased serum total antioxidant capacity (standardized mean difference [SMD] 0.62 mmol/L, 95% CI 0.18–1.05, I2 = 76.1%, p ˂ 0.001) and superoxide dismutase (SMD 0.40 U/mg, 95% CI 0.12–0.67, I2 = 9.6%, p ˂ 0.345) levels and decreased malondialdehyde (SMD –1.02 mmol/L, 95% CI –1.60 to –0.44, I2 = 88.2%, p ˂ 0.001) level significantly compared to the placebo group. Although the effect of CoQ10 on nitric oxide (SMD 1.01 µmol/L, 95% CI –1.53 to 3.54, p ˂ 0.001, I2 = 97.8%) and glutathione peroxidase (SMD –0.01 mmol/L, 95% CI –0.86 to 0.84, p ˂ 0.001, I2 = 88.6%) was not significant, CoQ10 can be mentioned as an improvement in antioxidant defense status against reactive oxygen species. Conclusion: These supplements have positive effects on antioxidant defense against oxidizing agents and elevate antioxidant enzyme levels in the body. However, due to limited research the results should be taken with caution.