Purpose: This study aimed to investigate the proportions of polypharmacy in the macroregions of Brazil, considering socioeconomic and demographic factors and their associations. Methods: A cross-sectional analysis was conducted using data from the second wave (2019–2021) of ELSI-Brazil. The outcome was self-reported polypharmacy. Independent variables included sociodemographic, health, and behavioral factors, such as diabetes and hypertension. Descriptive analyses incorporated sample weights, and Poisson regression was employed to assess associations between polypharmacy and the independent variables. Analyses were stratified by the five macroregions of Brazil: North, Northeast, Southeast, South, and Central-West. Results: Regional disparities in the prevalence of polypharmacy were observed. In the Central-West region, rural residents had a 16% lower prevalence of polypharmacy compared to urban residents (PR = 0.84, 95% CI [0.82–0.85]). In the North, non-white individuals had an 8% higher prevalence compared to white individuals (PR = 1.08, 95% CI [1.02–1.15]), while Black individuals had an 8% lower prevalence than white individuals (PR = 0.92, 95% CI [0.88–0.96]). Age also associated the prevalence of polypharmacy. Older adults aged 80 years or more had a 14% higher prevalence in the Southeast (PR = 1.14, 95% CI [1.08–1.19]) and a 17% higher prevalence in the South (PR = 1.17, 95% CI [1.08–1.27]) compared to younger age groups. Conclusion: This study identified regional disparities in polypharmacy prevalence across Brazil’s macroregions, influenced by factors such as age, chronic conditions, and socioeconomic status. Strengthening primary care, promoting rational medication use, addressing inequalities, and integrating prevention strategies are crucial to mitigating its negative impacts.