The thermomechanical fatigue (TMF) of single-crystal air-cooled turbine blades is critical for accurately evaluating the lifetimes of advanced aero-engines. The present work focuses on the mechanical behavior and damage mechanism of a single-crystal Ni-based superalloy (DD6) under stress-controlled TMF loading, and in-phase (IP) and out-of-phase (OP) mode of TMF were conducted and compared with low cycle fatigue (LCF) loading. A ratcheting effect is observed during the deformation of DD6 under TMF loading, and the direction and size of the ratcheting strain are considerably influenced by the phase angle and mechanical load. The ratcheting strain increases with mechanical load and dwell time at high temperature, consequently shortening the lifetime of the material. The key factors affecting the TMF damage of DD6 are identified through a SEM analysis, which shows that the damage under IP TMF loading mainly comes from creep and fatigue, whereas that under OP TMF loading is dominated by oxidation and fatigue. Based on the critical plane approach, a fatigue life prediction model is proposed considering the ratcheting effect to predict the fatigue life of DD6 under TMF loading. The good agreement between the proposed model and experimental data indicates that the model has the potential to predict the fatigue life of DD6 under TMF loading.