Thermal barrier coating (TBC) is crucial for the performance of single-crystal superalloys (SXs), which are prone to thermomechanical fatigue (TMF) failure under combined thermal and mechanical stresses. Despite this, the underlying mechanisms associated with oxidation-assisted crack propagation and interdiffusion-driven phase transformation in TBC/SX systems have not yet been fully elucidated, particularly regarding temperature effects. In this study, through integrated experimental efforts and state-of-the-art characterization techniques, the fatigue performance and relevant enhancement mechanisms of TBC/SX systems under representative conditions (520°C–900 °C and 600°C–980 °C) were comprehensively investigated. Results demonstrated that the TMF lifespan of SXs was substantially prolonged under all conditions with TBC application, exhibiting distinct temperature dependence, and primarily extending lifespan by prolonging the crack propagation stage. The exceptional oxidation resistance of the TBC layer played a crucial role in performance improvement by altering crack-front plasticity and mitigating oxidation-driven shear strain. Furthermore, the reduced coefficient of thermal expansion (CTE) mismatch between coating and substrate due to γ'-to-γ transformation, the enhanced capacity to release thermal stress resulting from α-Cr dissolution, and the uniform deformation across microstructures facilitated by the cross-slip of screw dislocations were considered as the main contributors to the more pronounced performance enhancement under high-temperature conditions. These findings provide a comprehensive understanding of the temperature-dependent TMF behavior and microstructural evolution mechanisms of TBC/SX systems, which gives new insights to excavate the design potential for multilayered coatings.