CF4 is one of the representative and environmentally hazardous perfluorinated compounds. Even though their decomposition via a catalytic thermal process is an effective process for dissociating C-F bonds by employing catalysts with Lewis acid sites, the related mechanisms are unclear. Herein, we report a theoretical mechanism for the hydrolysis of tetrafluoromethane (CF4) on an γ-alumina surface via density functional theory calculations. The overall reaction mechanism was divided into two steps: CF2O formation and CO2 formation. After the dissociative adsorption of CF4 to the strongest Lewis acid site on the surface of the catalyst, several pathways of defluorination reaction were investigated considering the presence of water and the order of reaction steps. Regardless of the reaction pathway considered, the rate-determining step of the overall reaction was found to be the first dissociation of the C-F bond in CF4, which has the highest energy barrier of 42.31 kcal/mol. Interestingly, oxygen vacancies were readily formed on the catalyst surface during several reaction pathways following its interaction with the reaction intermediate, and these sites could be replaced by fluorine atoms detached from CF4. Our findings suggest that facile desorption of HF, in addition to the presence of strong acidic sites on the catalyst surface for C-F bond dissociation, is critical for improving the CF4 hydrolysis.