Perfluorooctanoic acid (PFOA) has raised significant health concerns due to its high ecotoxicological risks and difficulties in removal by conventional water treatment process. Previous studies have demonstrated that photocatalytic techniques exhibit great potential in PFOA removal. However, the underlying mechanism of the degradation process has not been fully understood, particularly the contribution of the facet effects of catalysts. In this study, a combination of experiments and first-principles calculations were conducted to shed light on the facet-dependence of the interfacial interactions and oxidation during the PFOA degradation process. We proved that the interfacial interaction was essential in initiating the hole-dominated degradation process, and the {110}R3̅c facet of hexagonal In2O3 features the strongest interaction with PFOA. The overall defluorination rate was mainly controlled by the hole-dominated oxidation processes under UV irradiation, which were further attributed to the electronic structures and reaction site distributions of different In2O3 surfaces. This study provides molecular-level insights on the facet-dependent PFOA catalytic degradation process, which can guide the rational design of photocatalysts to achieve superior decontamination efficiency.