Thermal-mechanical fatigue (TMF) tests and isothermal fatigue (IF) tests were conducted using thin-walled tubular specimens under strain-controlled conditions. The results of TMF tests showed a strong correlation between mechanical behavior and temperature cycling. Under different phases of temperature and mechanical loading, the hysteresis loop and mean stress of the single crystal superalloy showed noticeable variations between the stress-controlled and strain-controlled conditions. In the strain-controlled TMF test, temperature cycling led to stress asymmetry and additional damage, resulting in a significantly lower TMF life compared to IF life at the maximum temperature. Moreover, the OP TMF life is generally lower than that of the IP TMF at the same strain amplitude. The Walker viscoplastic constitutive model based on slip systems was used to analyze the TMF mechanical behavior of the single crystal superalloy, and the change trends of the maximum Schmid stress, the maximum slip shear strain rate, and the slip shear strain range were analyzed, and their relationship with the TMF life was investigated. Finally, a TMF life prediction model independent of the loading mode and phase was constructed based on meso-mechanical damage parameters. The predicted TMF lives for different load control modes and phases fell within the twofold dispersion band.