What is Known and Objective: The use of multiple medications, or polypharmacy, is associated with an elevated risk of potential drug-drug interactions (pDDIs), consequently heightening the probability of adverse drug reactions. Currently, there is a dearth of data regarding pDDIs in Chinese patients with atrial fibrillation (AF) within real-world scenarios. This study is designed to investigate the existing state of polypharmacy and pDDIs in Chinese AF patients and to analyze the factors influencing pDDIs. Methods: This was a single-center retrospective investigation conducted at a tertiary hospital in China. Polypharmacy and pDDIs were examined based on the medications prescribed at the time of discharge. The pDDIs were assessed using the Lexi-Interact database and classified into Types A, B, C, D, and X. Results and Discussion: The study encompassed 802 AF patients. The median age was 73 years (ranging from 64 to 80). The most (72.7%) were 65 years or older, and 53.9% were male. The incidence rates of polypharmacy and excessive polypharmacy were 74.8% and 29.8%, respectively. At discharge, 69.0% of patients had at least one clinically relevant pDDI. There were 1820 (84.2%), 261 (12.1%), and 81 (3.7%) interactions categorized as Types C, D, and X, respectively. The most prevalent Type C interaction was the combined use of antihypertensive medications. Among Type D interactions, the most common was the combination of anticoagulants and antiplatelet drugs. The most frequent Type X interaction involved drugs that augmented the hyperkalemic effect. Through multivariate analysis, advanced age (p = 0.008) and a greater number of medications (p < 0.001) were significant predictors of pDDIs. What is New and Conclusions: Polypharmacy and pDDIs are widespread among AF patients. Advanced age and an increased number of drugs were determined to be predictive factors for pDDIs. The risk of DDIs can be reduced by decreasing the number of medications or opting for alternative drugs.