Background Physicians’ alert overriding behavior is considered to be the most important factor leading to failure of computerized provider order entry (CPOE) combined with a clinical decision support system (CDSS) in achieving its potential adverse drug events prevention effect. Previous studies on this subject have focused on specific diseases or alert types for well-defined targets and particular settings. The emergency department is an optimal environment to examine physicians’ alert overriding behaviors from a broad perspective because patients have a wider range of severity, and many receive interdisciplinary care in this environment. However, less than one-tenth of related studies have targeted this physician behavior in an emergency department setting. Objective The aim of this study was to describe alert override patterns with a commercial medication CDSS in an academic emergency department. Methods This study was conducted at a tertiary urban academic hospital in the emergency department with an annual census of 80,000 visits. We analyzed data on the patients who visited the emergency department for 18 months and the medical staff who treated them, including the prescription and CPOE alert log. We also performed descriptive analysis and logistic regression for assessing the risk factors for alert overrides. Results During the study period, 611 physicians cared for 71,546 patients with 101,186 visits. The emergency department physicians encountered 13.75 alerts during every 100 orders entered. Of the total 102,887 alerts, almost two-thirds (65,616, 63.77%) were overridden. Univariate and multivariate logistic regression analyses identified 21 statistically significant risk factors for emergency department physicians’ alert override behavior. Conclusions In this retrospective study, we described the alert override patterns with a medication CDSS in an academic emergency department. We found relatively low overrides and assessed their contributing factors, including physicians’ designation and specialty, patients’ severity and chief complaints, and alert and medication type.