CoMn spinel (CoMn) and Zn-substituted CoMn spinel (ZnCoMn) oxides were fabricated for revealing mechanism differences in acetone and propane catalytic oxidation. The temperature-conversion profiles, intrinsic reaction rate and activation energy convinced that CoMn and ZnCoMn exhibited high catalytic performance for acetone and propane oxidation, respectively. Experimental and theoretical investigation revealed that deep oxidation determined the acetone conversion, while the degradation of propane was governed by the fracture of C-H bond and subsequently the activation of C3H7. CoMn possessed more active lattice oxygen and superior oxygen activation capacity, allowing acetone to be directly converted into carboxylates without generating aldehydes. ZnCoMn with more high valence Mn species was conductive to the C-H bond dissociation and C3H7 activation. This work revealed the mutual relations between structure–property of the spinel oxides and reactivity of the diverse VOCs, which provided new insights for the rational design of spinel oxides for catalytic oxidation of diverse VOCs.