The composite dietary antioxidant index (CDAI) has been identified as a critical factor in the pathogenesis of certain inflammatory diseases. The study aimed to investigate the relationship between CDAI and Helicobacter pylori (H. pylori) infection using cross-sectional design. In this study, participants from the 1999-2000 National Health and Nutrition Examination Survey (NHANES) were analyzed using logistic and Cox regression analyses to assess the associations between H. pylori infection and CDAI, encompassing vitamin A, vitamin C, vitamin E, carotene, zinc, selenium, and copper. The results demonstrated a negative correlation between CDAI scores and H. pylori infection, revealing a non-linear relationship between the odds of H. pylori infection and CDAI as a continuous variable. Subsequently, a two-sample Mendelian randomization (MR) study was conducted utilizing genome-wide association study (GWAS) summary statistics to explore the causal relationship between antioxidant levels and H. pylori infection. We found that the intake of copper was a protective factor in the occurrence of H. pylori infection but did not support a causal association between circulating copper levels and H. pylori infection. The prevalence of H. pylori infection was found to be elevated among individuals of older age, lower education levels, limited socioeconomic status, smokers, diabetes, and those with hypertension. The study suggests that higher CDAI is linked to a decreased odds of H. pylori infection, and further prospective studies are needed to confirm the association. Our findings may have significant implications for the prevention and management of H. pylori-related diseases.