Background: Prescription medication usage has been used as a predictor of disease prevalence and overall health status. Evidence suggests an inverse relationship exists between polypharmacy, which is the use of 5 or more medications, and physical activity participation. However, there is limited evidence examining the relationship between sedentary time and polypharmacy in adults. The aim of this study was to examine the associations between sedentary time and polypharmacy in a large nationally representative sample of US adults. Methods: Study sample (N = 2879) included nonpregnant adult (≥20 y old) participants from the 2017–2018 National Health and Nutrition Examination Survey. Self-reported minutes per day of sedentary time were converted to hours per day. The dependent variable was polypharmacy (≥5 medications). Results: Analysis revealed that for every hour of sedentary time, there was 4% greater odds of polypharmacy (odds ratio, 1.04; 95% confidence interval, 1.00–1.07, P = .04) after adjusting for age, race/ethnicity, education, waist circumference, and the interaction term between race/ethnicity and education. Conclusion: Our findings suggest increased sedentary time is associated with an increased risk of polypharmacy among a large nationally representative sample of US adults.