In order to improve the reliability and service life of vehicle and diesel engine, the fatigue life prediction of the piston in a heavy diesel engine was studied by finite element analysis of piston, experiment data of aluminum alloy, fatigue life model based on energy dissipation criteria, and machine learning algorithm. First, the finite element method was used to calculate and analyze the temperature field, thermal stress field, and thermal–mechanical coupling stress field of the piston, and determine the area of heavy thermal and mechanical load that will affect the fatigue life of the piston. Second, based on the results of finite element calculation, the creep–fatigue experiment of 2A80 aluminum alloy was carried out, and the cyclic response characteristics of the material under different loading conditions were obtained. Third, the fatigue life prediction models based on energy dissipation criterion and twin support vector regression are proposed. Then, the accuracy of the two models was verified using experiment data. The results show that the model based on the twin support vector regression is more accurate for predicting the material properties of aluminum alloy. Based on the established life prediction model, the fatigue life of pistons under actual service conditions is predicted. The calculation results show that the minimum fatigue life of the piston under plain condition is 2113.60 h, and the fatigue life under 5000 m altitude condition is 1425.70 h.