Background: Virtual reality simulation (VRS) teaching offers nursing students a safe, immersive learning environment with immediate feedback, enhancing learning outcomes. Before the COVID-19 pandemic, nursing students had limited training and opportunities to care for patients in isolation units with infectious diseases. However, the pandemic highlighted the ongoing global priority of providing care for patients with infectious diseases.

Objective: This study aims to (1) examine the effectiveness of VRS in preparing nursing students to care for patients with infectious diseases by assessing its impact on their theoretical knowledge, learning motivation, and attitudes; and (2) evaluate their experiences with VRS.

Methods: This 2-phased mixed methods study recruited third-year undergraduate nursing students enrolled in the Integrated Emergency and Critical Care course at a university in Taiwan. Phase 1 used a quasi-experimental design to address objective 1 by comparing the learning outcomes of students in the VRS teaching program (experimental group) with those in the traditional teaching program (control group). Tools included an infection control written test, the Instructional Materials Motivation Survey, and a learning attitude questionnaire. The experimental group participated in a VRS lesson titled “Caring for a Patient with COVID-19 in the Negative Pressure Unit” as part of the infection control unit. In phase 2, semistructured interviews were conducted to address objective 2, exploring students’ learning experiences.

Results: A total of 107 students participated in phase 1, and 18 students participated in phase 2. Both the VRS and control groups showed significant improvements in theoretical knowledge scores (for the VRS group t46=–7.47; P<.001, for the control group t59=–4.04; P<.001). However, compared with the control group, the VRS group achieved significantly higher theoretical knowledge scores (t98.13=2.70; P=.008) and greater learning attention (t105=2.30; P=.02) at T1. Additionally, the VRS group demonstrated a statistically significant higher regression coefficient for learning confidence compared with the control group (β=.29; P=.03). The students’ learning experiences in the VRS group were categorized into 4 themes: Applying Professional Knowledge to Patient Care, Enhancing Infection Control Skills, Demonstrating Patient Care Confidence, and Engaging in Real Clinical Cases. The core theme identified was Strengthening Clinical Patient Care Competencies.

Conclusions: The findings suggest that VRS teaching significantly enhanced undergraduate nursing students’ infection control knowledge, learning attention, and confidence. Qualitative insights reinforced the quantitative results, highlighting the holistic benefits of VRS teaching in nursing education, including improved learning outcomes. The positive impact on student motivation and attitudes indicates a potentially transformative approach to nursing education, particularly in the post–COVID-19 era, where digital and remote learning tools play an increasingly vital role.