Substituting the anodic oxygen evolution reaction in water electrolysis with a thermodynamically more favorable ethanol oxidation reaction (EOR) provides a promising route for simultaneous biomass upgrading and energy-saving hydrogen production. Herein, we synthesize a NiOOH-CuO nano-heterostructure anchored on a three-dimensional conductive Cu foam, which exhibits remarkable EOR performance, surpassing all the state-of-the-art 3d transition-metal-based EOR electrocatalysts. Density functional theory reveals that the coupling between CuO and NiOOH by charge redistribution at the interface is critical, synergistically reducing the EOR energy barriers into an energetically favorable pathway. Conclusively, the hybrid water electrolysis cell using our catalyst as the anode (1) requires only a low cell voltage for H2 generation at the cathode and only liquid chemical production of acetate at the anode, and (2) shows a high ethanol conversion rate to acetate, which can readily be separated from the aqueous electrolyte by subsequent acidification and extraction processes.