Single-crystal nanocrystals of catalytic metals and oxides are essential for understanding chemical interactions on well-defined catalyst surfaces. However, a comprehensive understanding of the crystallographic origins for such enhancement has been lacking. This work provides formal evidence of the structure–property relationship through a model study on single-crystal TiO2. Our approach involves transient pulse heating to manipulate porosity and phase in epitaxially-grown TiO2 nanosheets along the (0 0 1) plane. Furthermore, we could introduce high-entropy alloy nanoparticles into the system, which exhibited excellent catalytic activity toward CO oxidation, achieving T90 at 143 °C. This improved performance is attributed to the interplay between the catalytic nanoparticles and the multiphase support, facilitating CO and O2 adsorption. Our study contributes to a fundamental understanding of structure–property relationships in heterogeneous catalyst systems. Overall, our thermal shock synthesis approach shows much promise for developing single crystal-based advanced nanocatalysts with broad practical implications.