Creep-fatigue experiments have been conducted in nickel-based superalloy GH720Li, one of the most important turbine disk materials, at an elevated temperature of 650°C with different grain sizes, to investigate the mechanism of grain size on the creep-fatigue life of GH720Li. Experimental results shows that the creep-fatigue life of GH720Li superalloy will decrease with the decrease of grain size. SEM fracture analysis indicates that the oxidation and cracking is the main mechanism of GH720Li in the process of creep-fatigue under high temperature, and the smaller of grain size will result in the longer length of grain boundary. Finally, two methods including the damage function based on hysteresis energy and the applied mechanical work density (AMWD) are modified to predict the creep-fatigue life of GH720Li, which match well with experimental data.