Background The influx of patients in the acute care setting with opioid use disorder (OUD) has outpaced many hospitals’ ability to educate interprofessional staff. This creates distressing experiences for interprofessional staff and patients, leading to moral distress and burnout in staff and poor patient outcomes. Objective The purpose of this study was to improve interprofessional staff knowledge, attitudes, and perceptions toward working with patients who have OUD using a blended classroom-simulation–based curriculum. Methods A preintervention and postintervention design was selected. Interprofessional staff (n = 46) participated in a blended classroom-simulation educational intervention focused on the neurobiology of OUD, stigma reduction, pain management, and harm reduction principles, followed by 3 high-fidelity simulation scenarios. Participants completed the Drug and Drug Problems Perceptions Questionnaire to measure staff self-perceived knowledge, skills, and attitudes when working with patients who use drugs before, immediately after, and again 3 and 6 months postintervention. Results Most respondents were nurses with an average of 7.6 (SD, 9.6) years of experience. The majority did not have prior training in substance use disorder before (75.6%). There was a statistically significant decrease in mean Drug and Drug Problems Perceptions Questionnaire scores across the total score mean: 55.2 (95% confidence interval, 52.2-58.3) versus 45.5 (95% confidence interval, 43.9-47.1), P < .001. Decreased score indicates improved attitude and perception. Discussion A curriculum consisting of a blended classroom-simulation intervention was successful at improving several domains regarding perceptions of caring for patients with OUD. This educational intervention can serve as a model for health care systems with goal of improving patient outcomes and staff well-being.