The oxidative and non-oxidative dehydrogenation of propane over a monolayer V2O5/TiO2 catalyst was examined using in situ Fourier transform infrared spectroscopy and pseudo in situ X-ray photoelectron spectroscopy (XPS). It was found that the freshly calcined catalyst contains vanadium in the V5+ state; however, its treatment in the propane flow leads to the reduction of V5+ to V3+. Simultaneously, the catalyst treatment in propane leads to the formation of Ti-O-H groups, the removal of vanadyl oxygen species, and accumulation of carbonaceous deposits. Besides, XPS data indicate that the reduction of catalyst is accompanied by reversible destruction of the vanadia monolayer and formation of 3D clusters or nanoparticles on the titania surface, which leads to catalyst deactivation. In contrast, under the action of a propane/oxygen mixture flow, the accumulation of carbonaceous deposits and the destruction of the vanadia monolayer do not proceed. In this case, V5+ cations are partially reduced to V4+, and the catalyst surface contains isopropoxide, acetone, formate, acetate, and carbonate species. We suggest that the oxidative dehydrogenation of propane to propylene over vanadium oxide-based catalysts proceeds via the redox mechanism, where the oxidized catalyst surface oxidizes propane and is reoxidized by gas-phase oxygen. The active sites contain V5+ cations, and the C-H bond of propane is activated preferentially on vanadyl oxygen species. The key intermediate is isopropoxide, which can transform to propylene or acetone. Adsorbed acetone is unstable and oxidized further to formate and acetate species, which could be oxidized to CO and CO2. In contrast, the non-oxidative dehydrogenation of propane proceeds over the reduced catalyst. In this case, active sites contain V3+ cations. The mechanisms of both reactions are discussed.