The C-H activation of methane remains a longstanding challenge in the chemical industry. Metal oxides are attractive catalysts for the C-H activation of methane due to their surface Lewis acid-base properties. In this work, we applied density functional theory calculations to investigate the C-H activation mechanism of methane on various sites of low-index facets of γ-Al2O3. The feasibility of C-H activation on different metal-oxygen (acid-base) site pairs was assessed through two potential mechanisms, namely, the radical and polar. The effect of surface hydroxylation on C-H activation was also investigated to examine the activity of γ-Al2O3 under realistic catalytic surface conditions (hydration). On the basis of our calculations, it was demonstrated that the C-H activation barriers for polar pathways are significantly lower than those of the radical pathways on γ-Al2O3. We showed that the electronic structure (s- and p-band center) for unoccupied and occupied bands can be used to probe site-dependent Lewis acidity and basicity and the associated catalytic behavior. We identified the dissociated H2 binding and final state energy as C-H activation energy descriptors for the preferred polar pathway. Finally, we developed structure-activity relationships for the C-H activation of methane on γ-Al2O3 that account for surface Lewis acid-base properties and can be utilized to accelerate the discovery of catalysts for methane (and shale gas) upgrade.