Introduction: The prevalence of polypharmacy is gradually increasing in geriatrics, which may contribute to adverse effects, such as potential drug–drug and drug–disease interactions. These side effects remain an important challenge in patient safety, which has a significant impact on mortality and incidence rate.Aims: Therefore, this study aims to understand the epidemiology of polypharmacy and identify factors that have an impact on the management of potentially inappropriate prescribing.Methods: This study is a cross-sectional study, analyzing the prescription data from 720 hospitalized patients aged 50+ with a random cluster sampling method. We used inverse probability treatment weighting (IPTW) method to group and match polypharmacy and non-polypharmacy patients, and logistic regression was conducted to explore the factors associated with polypharmacy.Results: The prevalence of polypharmacy accounted for 50.14% among the old patients in this study. Female patients (67.34%) have more polypharmacy than male patients, and key predictors associated with polypharmacy in the logistic regression model included the following: domicile (AOR = 0.63, 95% CI 0.42–0.95), annual income (AOR = 0.38, 95% CI 0.20–0.70), the number of chronic diseases (AOR = 3.68, 95% CI 2.69–5.06), taking Chinese medicine (AOR = 1.70, 95% CI 1.22–2.36), decision involvement (AOR = 1.49 95% CI 1.10–2.03), and depression (AOR = 1.42, 95% CI 1.03–1.96).Conclusion: Polypharmacy is common among the participants with chronic diseases in Hubei province, China. The study emphasizes that gerontology practitioners should be prudent in applying clinical guidelines to provide personalized, comprehensive assessment of decision making of prescriptions, especially in socioeconomically deprived areas.