Lutein, zeaxanthin, and β-cryptoxanthin are polar oxygenated carotenoids found to be detectable in more than 95% of the population in the United States. Research has linked these carotenoids with lower coronary heart disease prevalence. This study investigates the association of serum lutein/zeaxanthin and β-cryptoxanthin with erectile dysfunction (ED) among middle-aged and older men in the United States. Serum lutein/zeaxanthin and β-cryptoxanthin were independent variables. The outcome variable was ED. Analyzed data from 1,302 men (≥40 years old) who participated in the National Health and Nutrition Examination Survey 2001-2002 cross-sectional study were included. After adjusting for all covariates, serum lutein/zeaxanthin negatively correlated with ED (odds ratio [OR]: 0.972, 95% confidence interval [CI]: [0.951, 0.994], = .011). However, a U-shaped association between serum lutein/zeaxanthin and ED was detected in men with diabetes or prevalent cardiovascular disease. A U-shaped non-linear association was observed between β-cryptoxanthin levels and ED. These findings suggest that while both lutein/zeaxanthin and β-cryptoxanthin are recognized as essential antioxidants, maintaining lower serum lutein/zeaxanthin levels and appropriate serum β-cryptoxanthin levels may offer potential benefits for individuals with ED. Further investigations, particularly prospective studies, are warranted to determine the role of serum lutein/zeaxanthin and β-cryptoxanthin in the biological mechanism associated with ED.