It is difficult to have enough samples to implement the full-scale life test on the loader drive axle due to high cost. But the extreme small sample size can hardly meet the statistical requirements of the traditional reliability analysis methods. In this work, the method of combining virtual sample expanding with Bootstrap is proposed to evaluate the fatigue reliability of the loader drive axle with extreme small sample. First, the sample size is expanded by virtual augmentation method to meet the requirement of Bootstrap method. Then, a modified Bootstrap method is used to evaluate the fatigue reliability of the expanded sample. Finally, the feasibility and reliability of the method are verified by comparing the results with the semi-empirical estimation method. Moreover, from the practical perspective, the promising result from this study indicates that the proposed method is more efficient than the semi-empirical method. The proposed method provides a new way for the reliability evaluation of costly and complex structures.