An optimized version of the Maximum Variance Method (MVM) is employed to determine maximum shear stress amplitudes in high-cycle multiaxial fatigue analysis using the critical plane approach, increasing accuracy and reducing computational burden. This refined approach posits that the MVM assumes that the critical plane is the one subjected to the maximum variance of the shear stress history. Comprehensive statistical analyses, including Analysis of Variance (ANOVA) and multiple comparison techniques such as Tukey’s HSD and Bonferroni correction, were conducted to systematically investigate the impact of critical factors on fatigue resistance, such as mean stress, phase, synchrony, failure criteria, and the strategy for calculating maximum shear stress amplitude. These analyses highlighted significant effects of mean stress and phase on the accuracy of fatigue strength predictions, underscoring the effectiveness of the enhanced MVM in managing complex loading scenarios. The results demonstrate that the proposed methodology performs equal to or better than conventional methods, with significantly lower computational costs.