Objectives Given the many medications used to treat novel coronavirus disease (COVID-19) and its comorbidities and complications, the risk of drug-drug interactions (DDIs) and resulting patient harm is concerning. This study aimed to shed light on physicians' knowledge of potential DDIs related to COVID-19 treatment, to determine the effect of an information brief about these DDIs on their correct response rates, and to identify factors associated with higher levels of knowledge about these DDIs. Methods The knowledge of physicians regarding the clinical significance and intervention of 7 common potential DDIs during COVID-19 treatment was evaluated via an online survey. Using a pretest-posttest design, the physicians completed a multiple-choice questionnaire first using their existing knowledge, then received an information brief about the DDIs and completed the same questionnaire again. Pretest and posttest scores were evaluated and factors affecting correct response rates were determined using correlation, regression, and post-hoc analyzes. Results A total of 244 physicians participated in the survey, 147 (60.2%) of whom were involved in the treatment of COVID-19 patients. After the information brief, there were significant increases in the number of correct responses for both clinical significance and interventions (p< 0.0001). In comparisons of pretest knowledge, physicians involved in the treatment of COVID-19 patients showed significantly higher correct response rate for interventions compared to physicians who had not treated COVID-19 patients (p= 0.003). Post-hoc analysis to compare pretest correct intervention responses among all medical specialties revealed significant differences between infectious diseases and family practice (mean difference: 1.059;p= 0.005) and between internal medicine and family practice (mean difference: 1.771;p< 0.0001). Conclusion Physicians involved in the treatment of COVID-19 patients had more knowledge regarding clinical significance and appropriate management of potential DDIs than those not involved. Therefore, it may be beneficial to organize trainings and issue guidelines about potential DDIs for physicians during the COVID-19 pandemic.