In this work, the influence of the terminating or exposed crystal planes of anatase TiO2 support on the catalytic activity of Pt/TiO2 catalysts is reported. Strong effects were observed when using CO oxidation as a probe reaction. The CO oxidation activity over these catalysts ranks in the following order: Pt/TiO2-{101} > Pt/TiO2-{100} > Pt/TiO2-{001}. The combination of in situ X-ray absorption spectroscopy, X-ray emission spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, and density functional theory calculations unravelled a strong interaction between platinum particles and different dominating facets of anatase. The catalytic activity of the Pt/TiO2 catalysts can be correlated with the spectroscopic/structural results. Compared to {001} facets, the {100} and {101} facets of TiO2 can stabilize active highly dispersed Pt species and avoid sintering Pt particles. This finding provides some important insights into understanding the metal–support interfacial interactions of Pt/TiO2 catalysts for tuning their catalytic performance.