Oxidative stress and reactive oxygen species play a pivotal role in carcinogenesis. Recent studies have indicated a potential reduction in cancer incidence associated with antioxidant intake; however, these results remain controversial. We performed 2-sample Mendelian randomization (MR) analysis to explore the causal relationship between dietary antioxidant vitamins (retinol, carotene, vitamin C, and vitamin E), oxidative stress injury biomarkers (GST, CAT, SOD, and GPX), and the risk of colorectal cancer (CRC). The genetic instrumental variants (IVs) that had previously shown significant association with dietary antioxidant vitamins and oxidative stress injury biomarkers were screened from the UK Biobank and relevant published studies. The genome-wide association study (GWAS) data for total colorectal, colon, and rectal cancer were obtained from the FinnGen cohort. The primary MR analysis employed the inverse-variance-weighted (IVW) method. Furthermore, sensitivity analysis was performed to assess heterogeneity and horizontal pleiotropy. The results revealed no significant causal associations between dietary antioxidant vitamins, oxidative stress injury biomarkers, and the risk of CRC. The odds ratios (ORs) were as follows: 1.22 (95% confidence interval (CI): 0.65-2.28, P = .53) for retinol, 0.77 (95% CI: 0.50-1.18, P = .24) for carotene, 0.82 (95% CI: 0.42-1.63, P = .58) for vitamin C, and 1.20 (95% CI: 0.86-1.68, P = .28) for vitamin E. Regarding oxidative stress injury biomarkers, the ORs were 0.99 (95% CI: 0.93-1.06, P = .88) for GST, 0.99 (95% CI: 0.93-1.05, P = .65) for CAT, 1.02 (95% CI: 0.95-1.09, P = .57) for SOD, and 1.01 (95% CI: 0.95-1.07, P = .76) for GPX. Likewise, stratified analysis by tumor site revealed no beneficial effects in colon and rectal cancers. Our findings indicate that elevated levels of diet-related antioxidant vitamins, as well as biomarkers of oxidative stress injury, do not provide a protective effect against CRC risk.