Background: Drug-drug interaction is an emerging threat to public health. Currently, there is an increase in comorbid disease, polypharmacy, and hospitalization in Ethiopia. Thus, the possibility of drug-drug interaction occurrence is high in hospitals. This study aims to summarize the prevalence of potential drug-drug interactions and associated factors in Ethiopian hospitals. Methods: A literature search was performed by accessing legitimate databases in PubMed/MEDLINE, Google Scholar, and Research Gate for English-language publications. To fetch further related topics advanced search was also applied in Science Direct and HINARI databases. The search was conducted on August 3 to 25, 2019. All published articles available online until the day of data collection were considered. Outcome measures were analyzed with Open Meta Analyst and CMA version statistical software. Der Simonian and Laird's random effect model, I 2 statistics, and Logit event rate were also performed. Results: A total of 14 studies remained eligible for inclusion in systematic review and meta-analysis. From the included studies, around 8717 potential drug-drug interactions were found in 3259 peoples out of 5761 patients. The prevalence of patients with potential drug-drug interactions in Ethiopian hospitals was found to be 72.2% (95% confidence interval: 59.1, 85.3%). Based on severity, the prevalence of major, moderate, and minor potential drugdrug interaction was 25.1, 52.8, 16.9%, respectively, also 1.27% for contraindications. The factors associated with potential drug-drug interactions were related to patient characteristics such as polypharmacy, age, comorbid disease, and hospital stay. Conclusions: There is a high prevalence of potential drug-drug interactions in Ethiopian hospitals. Polypharmacy, age, comorbid disease, and hospital stay were the risk factors associated with potential drug-drug interactions.