The development of highly efficient and stable Co3O4-based electrocatalysts as promising alternatives to IrO2 for the acidic oxygen evolution reaction (OER) is needed to support broader commercialisation of a proton exchange membrane water electrolyzer (PEMWE). Unfortunately, the activity of Co3O4 is severely hindered by the linear scaling relationship through the favorable adsorbate evolution mechanism (AEM). Although considerable efforts have been devoted to promoting the oxygen pathway mechanism (OPM) to bypass the AEM pathway through tailoring the inherent structures of active sites on Co3O4, limited attention has been paid to the role of interfacial water molecules at the catalyst–electrolyte interface. Here, we demonstrate that the acidic OER pathway of Co3O4 can be rationally regulated through partial substitution of octahedral Co atoms in Co3O4 with Sb. We find that the asymmetric Sb–O–Co motif could induce interfacial H2O reorientation into H-down configuration, thus suppressing the nucleophilic attack of H2O molecules on the CoO* intermediate, which is the key for triggering the reaction pathway from the AEM to OPM. Consequently, the obtained Sb0.3Co2.7O4 catalyst exhibits remarkable OER activity and long-term durability, achieving 2 A cm−2 at 2.11 V and stable operation for over 800 hours at 2.0 A cm−2 in a PEMWE device.