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Introduction: Medical educators are constantly seeking methods to increase engagement in the era of coronavirus disease 2019 (COVID-19) where virtual and blended learning formats are increasingly common. Educational escape rooms have previously been used to motivate learners, enhance communication skills, and cultivate teamwork. However, it is not known whether escape rooms increase learner knowledge as compared to a lecture format. Methods: This quasi-experimental study included 30 emergency medicine residents at two programs who participated in both a virtual escape room and a lecture on infectious disease content. Learners completed a pre- and post-quiz and a tool to gauge resident motivation for each activity (the Intrinsic Motivation Inventory [IMI]). The primary objective was to determine a change in knowledge as a result of the activities, and a secondary objective was to determine resident motivation for each format. Results: At both programs learners demonstrated a significant improvement in their pre- vs. post-quiz scores for the escape rooms (University of California Irvine [UCI]: 77.8% to 88.9%, p = 0.028, Prisma: 73.81% to 89.68%, p = 0.002), whereas the lectures did not impact a statistical improvement (UCI: 73.8% to 78.6%, p = 0.460, Prisma: 85.71% to 91.27%, p = 0.236). Learners at UCI noted equivalent results on the IMI for both formats, while residents at Prisma noted they were more motivated by the escape room. Conclusion: Emergency medicine residents at two programs participating in a virtual escape room demonstrated a statistical increase in knowledge on infectious disease content as compared to a lecture format and reported positive motivation ratings for both formats, with one program preferring the escape room.