Introduction Simulation is increasingly being used in the preclinical years of US medical school curricula to provide experiential learning opportunities for students. However, preclinical medical students may not be able to access the full benefits of immersive simulation scenarios without an in-depth introduction to the simulation environment and manikin. An escape room may be an effective way to orient students in an interactive manner to overcome this barrier. Methods We designed and implemented a 90-minute escape room orientation activity to address student discomfort in the simulation environment by providing a team-based, hands-on exploration of identified critical features of the room and manikin in the guise of a routine clinic visit for a patient. We surveyed learners on their confidence immediately following the escape room and on their perceptions of the session effectiveness following their first simulation. Results A total of 148 preclinical medical students participated in the escape room activity in 30 groups of four to five persons. Of those students, 130 participated in a simulated patient case within 1 month of the escape room activity, and 89 filled out a follow-up survey. Of responding students, 80% reported that the escape room activity was highly effective or very effective in preparing them for participation in a simulated patient case. Discussion Implementing an escape room orientation activity for preclinical medical students was effective in preparing students to participate in their first immersive simulation scenario.