A efficient and low-cost nickel-based catalyst with abundant Ni/NiO heterojunctions was constructed and applied in the hydrodeoxygenation of phthalic anhydride to phthalide. The Ni/NiO heterojunction catalysts were prepared by treating mixed metal oxides derived from NiAl-LDH with different ratio in hydrogen at 400 °C, as confirmed by the XRD, H2-TPR, TEM and XPS characterization results. The developed Ni-NiO/Al2O3(3) sample with maximal Ni/NiO heterojunction possessed significant activity in phthalic anhydride hydrogenation with 99.7 % conversion and 90.6 % selectivity of phthalide at 170 °C and 4 MPa H2, as a result the amazing activity of 15.8 mmol·g−1·s−1 was achieved. Besides, Ni-NiO/Al2O3(3) catalyst exhibited good stability in this reaction, which indicated the Ni-NiO/Al2O3(3) catalyst haswideapplicationprospect in the hydrodeoxygenation of phthalic anhydride to phthalide. The Ni/NiO heterojunction in the catalyst was the key to achieve the amazing activity. Based on the kinetic analysis and theoretical calculations, the cooperative catalytic mechanism was found inthis reaction. The design of synergetic catalyst with dual-active-sites can by achieved by partly reduced with metal oxides.