The adsorption and dissociation of H₂S on MgO(100), Ni-doped MgO(100), and ZnO(0001) was studied using first-principles density-functional calculations (DFT-GGA) and periodic supercells. The bonding of H₂S and its S-containing dissociated species (HS and S) is substantially stronger on ZnO(0001) than on MgO(100), making dissociation easier on zinc oxide. This behavior can be explained by the smaller ionicity in ZnO, which leads to a larger electron density around the Zn atoms and a larger reactivity toward S-containing molecules. Replacing some of the metal centers of MgO(100) with Ni atoms enhances the binding of S-containing species through new electronic states associated with the Ni 3d levels and located above the occupied {O 2p + Mg 3s} bands. In addition, structural defects, like steps, expose metal centers with lower coordination and larger reactivity than pentacoordinated Mg atoms in MgO(100). A simple model based on perturbation theory and band−orbital mixing is able to explain the differences in the reactivity of MgO(100) and ZnO(0001) and the behavior of other oxides (Al₂O₃, Cr₂O₃, Cr₃O₄, Cu₂O) in the presence of sulfur-containing molecules. The model predicts a negative correlation between the reactivity of the oxides and the size of the electronic band gap, with the chemical activity of an oxide depending mainly on how well its bands mix with the orbitals of H₂S. The electrostatic interactions between the Madelung field of the oxide and the dipole moment of the molecule play only a secondary role in bonding.