Polypharmacy is associated with adverse drug reactions and represents an economic burden on the health insurance system. The objective of our study was to assess the trends in polypharmacy and its associated factors in South Korea. This cross-sectional study used a nationwide sampled database between 2002 and 2013, including outpatients of all ages who received at least 1 prescription in the same period. Polypharmacy was defined as the concomitant prescription of ≥6 distinct medications on a single prescription at least once without a given duration. The yearly prescribing trends were calculated and plotted. We conducted comparative analyses to identify the changes in social gradients of polypharmacy between the first 2 years, 2002‒2003, and the final 2 years, 2012‒2013. We repeated logistic regressions for pediatrics <20 years of age and adults ≥20 years of age to estimate the adjusted odds ratios (aOR) and 95% confidence intervals (CI). The distributions of polypharmacy in the respective periods were examined according to patient economic status (0 = most deprived and 10 = most affluent). The age-standardized prevalence of polypharmacy decreased from 65.8% in 2002 to 43.7% in 2013. Our study included 1,108,298 outpatients throughout 2002-2013. Pediatric patients aged 1-9 years had the highest number of medications among all age groups (mean: 5.1 ± 1.1 in 2002-2003 vs. 4.1 ± 1.1 in 2012-2013) in both periods. Changes in the association between deprivation and polypharmacy over 10 years were observed in adults (aOR = 0.68; 95% CI = 0.62-0.75 in 2002-2003 vs. 1.60; 95% CI = 1.54-1.66 in 2012-2013) and pediatrics (aOR = 0.60; 95% CI = 0.52-0.68 in 2002-2003 vs. 1.07; 95% CI = 1.01-1.14 in 2012-2013) compared with those in the most affluent patients. The high level of polypharmacy in pediatric patients is a public health concern that warrants policymaker attention.