Background: Polypharmacy, defined as concurrent use of five or more medications, affects nearly half of U.S. adults and is associated with adverse health outcomes. Most research examines prescription medications only, overlooking dietary supplement use despite its prevalence and potential for interactions. Additionally, little is known about whether polypharmacy-outcome associations differ across racial, ethnic, and socioeconomic groups. Purpose: This study examined associations between prescription polypharmacy and supplement polypharmacy with three cardiometabolic outcomes (hypertension, hyperlipidemia, hyperglycemia) among U.S. adults, and assessed whether associations varied by race/ethnicity and socioeconomic status. Methods: Cross-sectional data from 12,290 adults aged 18 years and older in the 2017-2018 National Health and Nutrition Examination Survey were analyzed. Prescription polypharmacy and supplement polypharmacy were defined as concurrent use of five or more prescription medications or dietary supplements, respectively. Self-reported physician diagnoses of hypertension, hyperlipidemia, and hyperglycemia served as outcomes. Survey-weighted logistic regression models adjusted for age, sex, race/ethnicity, education, socioeconomic status, body mass index, and smoking status were used to examine associations. Stratified analyses were conducted by race/ethnicity and socioeconomic status. Results: Weighted prevalence of prescription polypharmacy was 48.7%, and supplement polypharmacy was 11.3%. After adjustment, adults with hypertension were significantly more likely to have prescription polypharmacy (OR = 3.17, 95% CI: 2.35, 4.28) compared to those without hypertension. Similarly, adults with hyperlipidemia were significantly more likely to have prescription polypharmacy (OR = 1.95, 95% CI: 1.39, 2.73), and adults with hyperglycemia were significantly more likely to have prescription polypharmacy (OR = 3.80, 95% CI: 2.84, 5.08) compared to those without these conditions. Supplement polypharmacy was not significantly associated with any outcome. The likelihood of prescription polypharmacy among those with cardiometabolic outcomes varied by race/ethnicity, with particularly strong associations among Non-Hispanic Black adults with hyperglycemia (OR = 7.07), and remained significant across all socioeconomic strata. Conclusions: Prescription polypharmacy is highly prevalent and strongly associated with cardiometabolic outcomes. Adults with cardiometabolic conditions are substantially more likely to have prescription polypharmacy. On the other hand, supplement polypharmacy shows no such associations. Important disparities exist across racial/ethnic and socioeconomic groups. Findings support prioritizing prescription medication review in clinical practice and highlight the need for equity-focused medication management approaches.