To measure the prevalence and identify risk factors associated with drug-drug interactions among patients admitted to internal medicine departments in Palestinian hospitals. A retrospective cross-sectional observational study was conducted. Data were obtained from patient files from the internal medicine departments in Palestinian hospitals from 1 September 2017, to 31 March 2018. The data collected included patient gender, age, length of hospitalization, medications prescribed, and the number of medications. The digital clinical decision support system IBM Micromedex® was used to assess potential drug-drug interactions. The number of patients included in this study is 513. The total number of potential drug-drug interactions detected in study participants is 1558. The average number of potential drug-drug interactions per patient was found to be 3 ± 3.9. Among study participants, 66.1% (n = 339) were found to have potential drug-drug interactions in their current medications. The most commonly encountered drug-drug interactions type was "major" drug-drug interaction, which was encountered in 43.6% (n = 681) of total detected drug-drug interactions. Other types of drug-drug interactions were encountered in 42% (n = 647), 14% (n = 224), and 0.4% (n = 6) which were moderate, minor, and contraindicated drug-drug interactions, respectively. Patients' age, number of medications, and length of hospitalization were associated with the increased risk of potential drug-drug interactions. The results indicated a high prevalence of potential drug-drug interactions in Palestinian hospitals, associated with polypharmacy, increased age, and increased length of hospitalization. Therefore, managing patient medication by a drug expert such as a clinical pharmacist to identify and resolve potential drug-drug interactions will possibly decrease the high prevalence of drug-drug interactions, prevent patient harm, and decrease the cost of hospitalization.