A series of mixed cobalt spinel catalysts (M_xCo_3−xO₄ (M = Cr, Fe, Mn, Ni, Cu, Zn)) was synthesized and tested in the CO-PROX reaction and in sole CO oxidation and H₂ oxidation as references. The catalysts were thoroughly characterized by XRF, XRD, XPS, Raman, and IR spectroscopy, by TEM/STEM/EDX and with SEM techniques. Depending on the u parameter value (oxygen centricity between the tetra- and octahedral cations), two types of mixed spinel catalyst with distinctly different catalytic behavior in the CO-PROX reaction were distinguished. The A-type spinels (Co, Ni, Cu) with u ∼ 0.2625 exhibited overall higher activity in CO and H₂ oxidation and lower selectivity in the high-temperature range (T > 180 °C), whereas B-type spinels (Cr, Fe, Mn) with u < 0.2625 were less active yet more selective in the high-temperature range. The work function of the spinel catalysts was found to be a useful concise parameter in accounting for their CO-PROX performance, supporting the proposed categorization of the mixed spinels. Two heuristic descriptors, E_O2p + kΔ|<χ_M> − χ_O| and ΔE_M–O = (E_M3d − E_O2p), based on the position of the oxygen 2p (E_O2p) and the metal 3d (E_M3d) band centers and on the average metal <χ_M> and oxygen (χ_O) electronegativity difference, were proposed for the rationalization of the mixed spinel performance in terms of their intrinsic electronic properties. It was established that the activity depends on the volcano-type fashion of the ΔE_M–O values, whereas the selectivity is correlated with the E_O2p + kΔ|<χ_M> − χ_O| parameter in a monotonous fashion. The unique behavior of the Zn–Co spinel results from the lifting of the O2p center above the 3d band center of the redox Co³⁺ cations, in contrast to the other mixed spinel catalysts.