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Oxidative stress is a contributing factor to many chronic diseases. It has been investigated that zinc (Zn) may enhance the antioxidant defense. The current dose-response and time-response meta-analysis aims to determine the efficacy of Zn supplementation in improving antioxidant defense. Scopus, PubMed/Medline, Web of Science, and Embase databases were searched systematically up to December 30, 2020. Meta-analysis was performed on human controlled clinical trials using random effects method. To find any source of heterogeneity, subgroup analysis and meta-regression were performed. Trim and fill analysis was used for adjusting the publication bias. To find any non-linear relationship between variables and effect size, dose-response and time-response analyses were performed. Cochrane Collaboration's tool was used for evaluating the quality assessment. A total of 23 controlled clinical trials were analyzed. The range of Zn supplementation duration in various studies was within 4–24 weeks. Zn supplementation did not have beneficial effects on glutathione peroxidase (GPx) activity (SMD = −0.34 U/g; 95% CI: -0.93, 0.25; P = 0.258). There were significant increasing effects of Zn supplementation on glutathione (GSH) (SMD = 1.28 μmol/l; 95% CI: 0.42, 2.14; P = 0.003) and total antioxidant capacity (TAC) levels (SMD = 1.39 mmol/l; 95% CI: 0.44, 2.35; P = 0.004). Zn had ameliorative effects on superoxide dismutase (SOD) activity after elimination of publication bias (SMD: 0.84 U/g; 95% CI: 0.12, 1.56, P < 0.05). Zn could also elevate GSH and TAC levels, plus SOD activity after modifying the publication bias. Finally, Zn had no significant effect on GPx activity. [ABSTRACT FROM AUTHOR]