<p>We investigated thermally driven reactions at the Cr/Bi₂Se₃ interface via atomic-resolution scanning transmission electron microscopy, revealing that structural transformations were strictly dictated by Bi cation enrichment. Under mild heating at 150 °C, the selective reaction between Cr and Se, where Cr substituted for Bi, resulted in a low degree of Bi cation enrichment. These displaced Bi cations segregated at the reaction front and formed a layer of pure Bi, yielding an atomically sharp CrSe₂/Bi/Bi₂Se₃ epitaxial heterostructure. Conversely, a higher temperature of 350 °C induced high Bi cation enrichment due to the significant growth of the CrSe₂ layer and the massive displacement of Bi. This excess Bi disrupted the flat interface, forming a BiSe phase near the boundary and alternating Bi₃Se₄/Bi₂Se₃ superlattices deeper within the substrate. Simultaneously, the significant disparity in diffusion rates (<i>v</i>_<i>Cr</i> ≫ <i>v</i>_<i>Se</i>) triggered the Kirkendall effect, leading to macroscopic void formation. Our findings highlight that controlling cation enrichment critically influences the interfacial structure during solid-state reactions.</p>