Background: With increasing life expectancy, the number of older adults with multiple chronic conditions requiring complex medication regimens is growing, raising concerns about polypharmacy and potentially inappropriate medication (PIM) use. This study investigated trends in polypharmacy and PIM use among 66-year-olds in South Korea from 2012 to 2021, considering participant characteristics, to inform interventions and policies. Methods: A repeated cross-sectional study was conducted using the National Health Insurance Services database covering approximately 97% of Koreans. We included 3,397,044 individuals aged 66 who underwent the National Screening Program for Transitional Ages between 2012 and 2021. Polypharmacy was defined as the use of ≥5 medications for ≥90 days annually, hyper-polypharmacy as ≥10 medications, and PIM use as ≥1 PIM for ≥28 days. Trends were analyzed by sex, frailty, comorbidity, income, insurance type, and residence. Results: Polypharmacy prevalence increased from 32.0% in 2012 to 35.4% in 2021, and hyper-polypharmacy also rose. PIM use slightly decreased from 55.7% to 53.7%. Higher rates of polypharmacy and PIM use were observed among rural residents, medical aid beneficiaries, and those with lower income. Despite improvements in comorbidity and frailty, socioeconomic disparities widened, particularly among medical aid beneficiaries. Frequently prescribed PIMs included NSAIDs, PPIs, muscle relaxants, and anxiolytics/hypnotics. Conclusion While PIM use slightly decreased over the study period, it remained above 50%, and polypharmacy prevalence increased among older adults in Korea. Socioeconomic disparities in medication use persist, highlighting the need for targeted interventions and policies to promote safe medication use among vulnerable groups.