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Abstract Background Since COVID-19 limits safe clinical practice settings, virtual reality (VR) emerged as an alternative to practical education. Using VR simulation to learn mechanical ventilation is rare in nursing education. Methods This study developed a VR simulation program for mechanical ventilation care and evaluated its effects. We adopted a quasi-experiment design. Participants were fourth-year students across nursing colleges in South Korea. Results The interaction effect of the intervention time point and control group, to which the VR simulation program was applied, showed a significant difference in self-efficacy (F = 19.54, p < .001) and clinical reasoning capacity (F = 16.97, p < .001). Learning satisfaction of the experimental group was statistically significantly higher than that of the control group(F = 5.22, p = .026). The level of learning immersion (t = − 3.13, p = .003) and learning satisfaction (t = − 3.49, p = .001) were statistically significantly higher in the experimental group than in the control group. Conclusion These findings confirmed that the VR stimulation program for nursing students had a positive effect on their self-efficacy, clinical reasoning capacity, and learning satisfaction. Furthermore, it was effective in improving their nursing competence.