The exfoliation of 2D nanomaterials from 3D multimetal oxides with a stable structure is a great challenge. Herein, a delafossite CuFeO2+δ nanosheet becomes an open-layered structure by introducing excess oxygen so that the 2D Janus CuFeO2+δ single layer can be further obtained by aqueous ultrasonic exfoliation. The 2D Janus CuFeO2+δ single layer breaks the limitation of mirror symmetry, which is very beneficial to the effective separation of photogenerated electron-hole pairs. Serving as both a photoelectrode and a photocatalyst, the 2D Janus CuFeO2+δ single layer/few layer remarkably enhances the photocatalytic activity with long-term stability: the photocurrent density is increased by 2-fold, and the rate of H2 evolution is increased by 1.5-fold, in comparison with the counterpart of unexfoliated CuFeO2+δ nanosheets. This work demonstrates that 2D nanomaterials can be directly exfoliated from 3D nanomaterials by rational composition and microstructure design, which is helpful in promoting the development of bimetallic-oxide-ene (BMOene) as a novel functional material.