Interface engineering of transition metal layered double hydroxides (LDHs) is an effective method in the development of promising catalysts for enhancing their electrochemical activity toward the oxygen evolution reaction (OER). Herein, a multi-interface strategy is proposed to boost the OER performance of NiFe-LDH by constructing NiFe-LDH with carbon nanospheres and CeO2 nanomaterials. This method couples NiFe-LDH with CeO2 and carbon to form a NiFe/CeO2/C heterostructure and reconstructs the electronic structure, accompanied by the generation of oxygen vacancies. Heterostructure interface and vacancy synergy enhance the electronic interactions and improve the electrochemical activity of the OER process. Optimized 8NiFe/2CeO2/C shows a low overpotential of 247 mV at the current density of 10 mA cm−2, a Tafel slope of 78.0 mV dec−1, and robust operating durability in 1 M KOH electrolyte. The strong electronic transport pathway between NiFe-LDH and CeO2 improves the electron transfer rate, exposes more active centers, and fastens mass transfer. This study provides a practical strategy for developing efficient, stable, and low-cost electrocatalysts.