<p>Inappropriate prescribing of medicines could result in adverse drug reactions and interactions thereby leading to morbidity and mortality. Potential drug-drug interactions are preventable drug-related problems with the risks of hospitalization, adverse effects, and treatment failure. This study aimed to assess medication utilization patterns, and potential drug-drug interactions and its determinants among outpatient prescriptions. A cross-sectional survey was conducted. The study included dispensed outpatient prescriptions in six community chain pharmacies in Asmara, Eritrea, between June 16 and July 16, 2023. A stratified random sampling was utilized and drug interactions were screened using Lexi-comp drug interaction checker. Logistic regression was used to assess the determinants of clinically significant potential drug-drug interactions using IBM SPSS (version-26.0). A total of 417 outpatient prescriptions were included in the study. Moreover, a total of 830 medicines were prescribed from the 417 dispensed outpatient prescriptions. The most commonly prescribed medicines were omeprazole (8.4%) and amoxicillin (8.1%). Out of 267 prescriptions containing two or more medicines, the prevalence of clinically significant pDDIs was 29.2% (95%CI: 23.7, 34.7). The most common medicines involved in clinically significant pDDIs were diclofenac (22.6%) and ciprofloxacin (10.9%). Adult population (AOR = 4.23, 95%CI: 1.49, 12.01), older adult population (AOR = 7.09, 95%CI: 2.24, 22.44), number of drugs prescribed (AOR = 2.27, 95%CI: 1.53, 3.37), and tertiary level health facility (AOR = 9.13, 95%CI: 1.17, 71.42) were significant determinants of clinically significant pDDIs. Clinically significant pDDIs were detected in considerable number of outpatient prescriptions requiring strict monitoring from healthcare professionals, policy makers, and program managers.</p>