Bulk V-Nb-O, Mo-Nb-O, Te-Nb-O, and V-Mo-Te-Nb-O mixed metal oxides were synthesized and characterized with Raman spectroscopy, XRD, and BET methods. The interaction of the V and Mo cations with the Nb2O5 lattice followed three stages: (1) cations were initially incorporated into the Nb2O5 lattice forming a solid solution or compound as well as on the Nb2O5 surface, (2) a two-dimensional surface cation overlayer was formed after saturation of the solid solution, and (3) microcrystalline metal oxide phases (e.g., V2O5 and MoO3) were formed after completion of the two-dimensional surface cation monolayer. The catalytic properties of these bulk mixed metal oxides were investigated for the oxidative dehydrogenation (ODH) of propane to propylene, and their activity follows the trend: V-Nb-O > Mo-Nb-O much greater than Nb2O5 > Te-Nb-O. The highest propane conversions and propylene yields were found when the two-dimensional surface metal oxide monolayers were formed, which suggests that the surface metal oxide species are the surface active sites in these bulk mixed metal oxide catalysts for propane ODH. Furthermore, the number of surface active sites present in the bulk mixed metal oxides was determined by comparative studies between the bulk mixed metal oxides and the corresponding model Nb2O5-supported metal oxides. These numbers can be used further for the calculation of the TOF (turn-over-frequency) values and quantitative comparison of the catalytic behavior of the different bulk mixed metal oxide catalysts for propane ODH. The catalytic results over the model Nb2O5-supported metal oxides demonstrate that the propane ODH reaction is structure insensitive because the TOF is independent of the number and the structure of surface active sites. The composition and calcination temperature of the bulk mixed metal oxide catalysts affects the surface density of the active sites, which controls their catalytic behavior for propane ODH.