: Effective infant cardiopulmonary resuscitation (CPR) relies on high-quality chest compressions, yet the optimal technique for single-rescuer scenarios remains debated. Although widely used, the two-finger technique (TFT) is associated with an inadequate compression depth and increased rescuer fatigue. While the two-thumb encircling hands technique (TTHT) provides a superior compression depth, its application in single-rescuer scenarios is impractical. This study evaluates a novel technique (nT) as a potential alternative, aiming to optimize both compression efficacy and rescuer endurance. : This randomized crossover study assessed the efficacy of the TFT, TTHT, and nT in a simulated infant CPR setting. Medical students trained in newborn and infant resuscitation performed all three techniques in a controlled environment using a high-fidelity neonatal simulator. We objectively measured and compared key CPR performance metrics, rescuer fatigue, and hand pain among the techniques. : The nT and TTHT outperformed the TFT in compression depth, rescuer endurance, and overall CPR quality. The nT achieved the highest adequate compression rate (92.4% vs. 78.6% for TTHT and 65.2% for TFT) while minimizing fatigue (RPE: 3.1 vs. 4.5 for TTHT and 6.2 for TFT) and hand pain (NRS: 1.8 vs. 3.9 for TTHT and 5.4 for TFT). TTHT produced the deepest compressions (mean: 44.2 mm vs. 42.9 mm for nT and 38.6 mm for TFT, < 0.001). Rescuer anthropometric factors (sex, weight, and height) affected all techniques similarly, suggesting no inherent advantage based on body characteristics. : Both the nT and TTHT outperformed the TFT, with the nT demonstrating superior rescuer endurance while maintaining high-quality compressions. Given its ergonomic benefits and effectiveness, the nT emerges as a promising alternative for single-rescuer infant CPR and warrants consideration for future resuscitation guidelines.