Despite the routine use of high-fidelity patient simulation (HFPS) in health care disciplines, pharmacy residents' involvement in HFPS is limited. To evaluate pharmacy residents' self-reported confidence in their clinical skills dealing with acute medical scenarios. Three separate HFPS sessions (stroke, Advanced cardiovascular life support [ACLS], and acetaminophen poisoning) were conducted for pharmacy residents at a designated simulation center using a high-fidelity mannequin. The scenarios were facilitated by experienced physicians, nurses, and clinical pharmacists. A questionnaire that addressed 5 clinical skills was administered to the residents pre- and post-HFPS and 6 months afterward. The primary outcome was an assessment of residents' confidence in acute medical scenarios. Fourteen pharmacy residents participated (mean age of 27.7 years; 71.4% female; 57% have [greater than or equal to]3 years of work experience as a pharmacist). Around 85.6%, 78.6%, and 64.3% of the residents had encountered stroke, ACLS, and acetaminophen poisoning cases, respectively, before the HFPS. After the HFPS sessions, the residents felt significantly more confident in making decisions during an emergency in a timely manner (P = 0.006 for stroke; P = 0.02 for poisoning), providing recommendations to the health care team (P = 0.006 for stroke; P = 0.024 for ACLS), and providing optimal patient care during a stressful situation (P = 0.02 for stroke and poisoning). We found no significant difference between post-simulation and 6 months post-simulation scores in most of the domains in all scenarios, indicating residents' confidence was maintained at 6 months. HFPS is a valuable active learning tool for enhancing pharmacy residents' confidence in managing an emergency situation.