Regulating the metal–support interaction is essential for obtaining highly efficient catalysts for the catalytic oxidation of volatile organic compounds (VOCs). In this work, CuO-TiO2(coll) and CuO/TiO2(imp) with different metal–support interactions were prepared via colloidal and impregnation methods, respectively. The results demonstrated that CuO/TiO2(imp) has higher low-temperature catalytic activity, with a 50% removal of toluene at 170 °C compared to CuO-TiO2(coll). Additionally, the normalized reaction rate (6.4 × 10−6mol·g−1·s−1) at 160 °C over CuO/TiO2(imp) was almost four-fold higher than that over CuO-TiO2(coll) (1.5 × 10−6mol·g−1·s−1), and the apparent activation energy value (27.9 ± 2.9 kJ·mol−1) was lower. Systematic structure and surface analysis results disclosed that abundant Cu2+active species and numerous small CuO particles were presented over CuO/TiO2(imp). Owing to the weak interaction of CuO and TiO2in this optimized catalyst, the concentration of reducible oxygen species associated with the superior redox property could be enhanced, thus significantly contributing to its low-temperature catalytic activity for toluene oxidation. This work is helpful in exploring the influence of metal–support interaction on the catalytic oxidation of VOCs and developing low-temperature catalysts for VOCs catalytic oxidation.