Background: Over the past decade, the use of technology-enhanced simulation in emergency medicine (EM) education has grown, yet we still lack a clear understanding of its effectiveness. This systematic review aims to identify and synthesize studies evaluating the comparative effectiveness of technology-enhanced simulation in EM. Methods: We searched MEDLINE, EMBASE, PsycINFO, CINAHL, ERIC, Web of Science, and Scopus to identify EM simulation research that compares technology-enhanced simulation with other instructional modalities. Two reviewers screened articles for inclusion and abstracted information on learners, clinical topics, instructional design features, outcomes, cost, and study quality. Standardized mean difference (SMD) effect sizes were pooled using random effects. Results: We identified 60 studies, enrolling at least 5279 learners. Of these, 23 compared technology-enhanced simulation with another instructional modality (e.g., living humans, lecture, small group), and 37 compared two forms of technology-enhanced simulation. Compared to lecture or small groups, we found simulation to have nonsignificant differences for time skills (SMD 0.33, 95% confidence interval [CI] −0.23 to 0.89, n = 3), but a large, significant effect for non–time skills (SMD 0.82, 95% CI 0.18 to 1.46, n = 8). Comparison of alternative types of technology-enhanced simulation found favorable associations with skills acquisition, of moderate magnitude, for computer-assisted guidance (compared to no computer-assisted guidance), for time skills (SMD 0.50, 95% CI −1.66 to 2.65, n = 2) and non–time skills (SMD 0.57, 95% CI 0.33 to 0.80, n = 6), and for more task repetitions (time skills SMD 1.01, 95% CI 0.16 to 1.86, n = 2) and active participation (compared to observation) for time skills (SMD 0.85, 95% CI 0.25 to 1.45, n = 2) and non–time skills (SMD 0.33 95% CI 0.08 to 0.58, n = 3). Conclusions: Technology-enhanced simulation is effective for EM learners for skills acquisition. Features such as computer-assisted guidance, repetition, and active learning are associated with greater effectiveness.