Background: Clinical simulation is a promising teaching strategy for cardiopulmonary resuscitation (CPR) training and basic life support (BLS) education. However, the effectiveness of different simulation-based methods in CPR training requires further exploration. Objective: This study compares the effectiveness of three simulation-based methods-game-based virtual reality (VR), high-fidelity simulation (HFS), and low-fidelity simulation (LFS)-on CPR performance, BLS knowledge retention, and skills acquisition in nursing students. Methods: Ninety undergraduate nursing students were randomized into three groups (VR, HFS, LFS; n = 30 each). After standardized theoretical training, students underwent practical training in CPR techniques, including chest compressions and automated external defibrillator (AED) use, based on their assigned method. Knowledge was assessed pre- and post-training and at three- and six-months. Skills were evaluated immediately post-training. Qualitative feedback was collected to gain insights into student experiences. Results: All groups showed significant CPR knowledge and skill improvement improvement post-training (p < .05). The VR group had significantly higher knowledge retention at three and six months (p = .035, p = .018) and higher skills scores compared to HFS and LFS (p < .001). Satisfaction and self-confidence scores were not statistically different but were higher in the VR group. Student feedback highlighted VR's realistic, immersive nature in CPR training. Conclusion: Game-based VR simulation effectively enhances and retains CPR knowledge and skills and offers a cost-effective, innovative alternative to LFS and HFS. (c) 2025 International Nursing Association for Clinical Simulation and Learning. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.