The high-temperature structure of aero-engine usually works in the environment of high temperature and fatigue load, which leads to a very complicated crack problem. This paper presents mixed-mode fatigue crack growth (FCG) experiments conducted on compact tension shear (CTS) specimens made of a nickel-based superalloy at 550 °C, with varying thicknesses. The influence of thickness on mixed-mode FCG behavior was investigated by experiments and finite element method (FEM) analysis. The expanded FCG model, which considers thickness effects based on closure theory, provides a more precise prediction of crack growth rates for mixed-mode loading conditions. In addition, it is observed that the mixed-mode FCG da/dN-ΔK curve for nickel-based superalloys shifts vertically as the specimen thickness varies, and the thickness has no effect on the mixed-mode FCG angle. This achievement has made a significant contribution to the damage tolerance design of aircraft engines.