This study developed a VOC (methyl ethyl ketone (MEK)) removal catalyst and examined it computationally and experimentally. Computational screening, focusing on CH4 adsorption, showed that Pt-substituted TiO2(110) surface strongly attracts CH4 (Eads = 51.1 kJ/mol), facilitating initial CH bond cleavage on the surface. The predicted screening results suggested that Pt-substituted TiO2(110) would also be highly active toward MEK combustion because the catalysts activating the highly stable molecule of methane would have a high potential to activate MEK with weaker CH bonds compared to methane. The further in-depth computational analysis exploring the adsorption energies (Eads = 63.9 kJ/mol (0Pt) → 122.8 kJ/mol (1Pt) → 152.9 kJ/mol (2Pt)), the dissociation kinetics of adsorbed MEK and O2 confirmed the high reactivity toward MEK combustions on Pt-substituted TiO2; CH bond cleavage of MEK occurs with low energy barriers of <∼55 kJ/mol. Finally, the computational results were verified experimentally. The experimental results showed that sol–gel prepared Pt/TiO2 catalyst provides an enhanced reactivity than the widely used impregnated catalyst for VOCs removal, and its high reactivity stems from the Pt-substituted site in TiO2. The proposed high reactivity of Pt-substituted TiO2 would provide fundamental and applicative insights to improve the reactivity by reducing the cost of developing VOCs removal catalysts using noble metal elements. Beyond the development of VOCs removal catalysts, we believed that the proposed approach combined with computational screening, in-depth computational analysis, and experimental verifications would be a promising and practical strategy for developing other catalysts.