AbstractThis work reports the formation of a heterojunction composed of Tl2Ba2CaCu2O8 (Tl‐2212) and Bi2Se3 as the high critical temperature superconductor and topological insulator, respectively. The Bi2Se3 film is deposited on the Tl‐2212 by a chemical mechanical polishing process. Due to the rough surface of Tl‐2212, the treated Tl‐2212 is then subjected to post‐annealing at various temperatures. This temperature does not affect the formation of the interfacial layer at the heterojunction; however, an improved layered crystal structure of the Bi2Se3 film is observed at 500 °C. The in‐depth profile of the relative atomic concentration indicates the diffusion of Cu and Tl into the Bi2Se3 film with the Ba diffusion being closer to the interfacial layer. At 500 °C, Cu atoms are more actively diffused into the Bi2Se3 film, thus blocking Tl diffusion, and improving the layered crystal structure of the film. The density functional theory calculations reveal that the lowest formation energy of the Cu vacancy is when Bi2Se3 is in contact with Tl‐2212, which results in the diffusion of Cu atoms from Tl‐2212, thus transforming the interstitial Cu atoms into the film. These atoms have an n‐type doping effect and prefer intercalating at a vdW gap deep inside the layered Bi2Se3.