Cancer survivors are motivated to change lifestyle following diagnosis, but studies investigating the outcomes are scarce. The purpose of this study was to examine the associations between antioxidant supplementation and quality of life (QoL) in stage-II colorectal cancer survivors. Four-hundred-fifty-three survivors were enrolled from the North Carolina Cancer Registry from 2009 to 2011. Interview data on demography, treatment, health behaviors, and QoL were collected at diagnosis, and at 12 and 24 mo post-diagnosis. Antioxidant supplementation was self-reported as use of selenium, zinc, beta-carotene, vitamin A, vitamin E, or vitamin C at baseline. Two-hundred-sixty-one subjects completed the 24-mo interview. After adjusting for multiple confounders, there was no association between antioxidant use and the Functional Assessment of Cancer Treatment-Colorectal [β = 1.41; 95% confidence interval (CI): -2.48, 5.30] or the medical outcomes 12-item short form (physical composite score: β = 0.84; 95% CI: -1.39, 3.07; mental composite score: β = -0.61; 95% CI: -2.65, 1.43). This study revealed no benefit of antioxidant use among survivors, possibly explained by a limited sample size of antioxidant users. More prospective studies are necessary to assess the benefits of antioxidants.