Catalytic C–O bond hydrogenolysis is an essential route to produce sustainable chemicals and fuels from lignin and its derivatives. Herein, various Ni-based catalysts were successfully prepared and evaluated in the C–O bond hydrogenolysis of lignin-derived diphenyl ether (DPE) and benzyl phenyl ether (BPE). It is found that 10%Ni/α-Al2O3 shows the highest activity for cleaving C–O bonds of DPE and BPE at low reaction temperatures and low H2 pressures. Compared to 10%Ni/γ-Al2O3 and 10%Ni/γ-Al2O3-2, 10%Ni/α-Al2O3 exhibits a higher initial reaction rate for the conversion of DPE and BPE. Different characterizations reveal that the high activity of 10%Ni/α-Al2O3 is ascribed to relatively electron-rich Ni metals, providing a large number of Ni–Ni bonds, which is mainly responsible for a rapid H2 adsorption–activation–dissociation and for driving substrate hydrogenolysis. Furthermore, 10%Ni/α-Al2O3 not only catalyzes C–O bond hydrogenolysis of other lignin derivatives but also achieves the depolymerization of real lignin to produce guaiacol with a high yield.