Modulating the metal–support interaction is a promising way to tailor the electronic structure of metal nanoparticles and hence alter their catalytic performance. Here, we developed a reduced TiO2 with rich oxygen vacancies on which to load Pd for catalytic oxidation of formaldehyde (HCHO) at room temperature. The reduced TiO2 remarkably induced an electronic metal–support interaction by transferring electrons from the support to Pd to form negatively charged Pd nanoparticles, facilitating the oxygen association. Simultaneously, the reduced TiO2 significantly increased the dispersion and the reduction degree of Pd compared with the pristine TiO2 by offering more anchor sites and electron-rich sites. Furthermore, the abundant oxygen vacancies in the reduced TiO2 show a synergistic effect by enabling the effective adsorption and dissociation of water to generate surface hydroxyl groups, accelerating the kinetics of active oxygen species generation and promoting the complete conversion of 100 ppm HCHO at a WHSV of 120,000 mL/(gcat·h). We tentatively propose two reaction mechanisms for HCHO oxidation over Pd-loaded oxygen-vacancy-rich TiO2 involving active oxygen species.