This study investigates the microstructural evolution and damage mechanisms of the nickel-based single-crystal superalloy DD9-thermal barrier coating (TBC) system under 1050 °C high-temperature oxidation, while conducting a comparative analysis of oxidation behavior with the DD6-TBC system. Results show that both systems have similar oxidation mechanisms but face long-term oxidation drawbacks: as oxidation time increases, the thermally grown oxide (TGO) evolves into a mixed oxide layer and an Al₂O₃ layer, with initial rapid TGO growth consuming Al in the bond coat (BC) and subsequent Al depletion slowing growth, though long-term TGO accumulation raises cracking and spallation risks. DD9 and DD6 substrates significantly affect substrate-BC interfacial interdiffusion: the interdiffusion zone (IDZ) and secondary reaction zone (SRZ) grow continuously (SRZ growing faster), and linear topologically close-packed (TCP) phases precipitate in the SRZ, spreading throughout the substrate and impairing high-temperature mechanical properties. Specifically, DD9’s IDZ growth rate is faster than DD6’s in the first 800 h of oxidation but slows below DD6’s afterward, reflecting DD9’s superior long-term oxidation resistance due to better temperature resistance and high-temperature stability. This study clarifies key high-temperature service disadvantages of the two systems, providing experimental support for coated turbine blade life evaluation and a theoretical basis for optimizing third-generation single-crystal superalloy-TBC systems to enhance high-temperature service stability.