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This paper aims to determine the relationship between thermodynamic entropy generation and fatigue crack propagation life of superalloy GH4169 at 300–650°C. The entire specimen was considered as the thermodynamic system. The plastic energy dissipation in the crack tip was obtained by finite element simulation utilizing the Chaboche nonlinear hardening model. Then the cyclic entropy generation rate (CEGR) and the accumulated entropy generation are calculated by combining simulation and experimental methods. Results show that the CEGR is a power function of the stress intensity factor range, and it is almost a constant at fatigue failure. The fatigue fracture entropy (FFE) increases as fatigue cycles at failure increase at constant temperature, but it first decreases and then increases when temperature increases from 300 to 650°C. A fatigue life prediction model based on the thermodynamic damage parameter is established and verified by comparison with experimental results and available data in the literature. Highlights: Thermodynamics provides a new thought to the study of elevated temperature crack growth.The Chaboche nonlinear hardening model is considered in entropy generation calculation.An entropy‐based damage parameter can represent the damage of a thermodynamic system.Entropy‐based life prediction model can acceptably predict the crack propagation life. [ABSTRACT FROM AUTHOR]