Supported Ni/Al2O3 catalysts are widely used in chemical industries. Regeneration of the deactivated Ni catalysts caused by sintering of Ni nanoparticles and carbon deposition after long-term operation is significant but still very challenging. In this work, a feasible strategy via solid-phase reaction between NiO and Al2O3 followed by a controlled reduction is developed which can burn out the deposited carbon and re-disperse the Ni nanoparticles well, thus regenerating the deactivated Ni catalysts. To demonstrate the feasibility of this method, Ni catalyst supported on alpha-Al2O3 (Ni/Al2O3) for CO methanation reaction was selected as a model system. The structure and composition of the fresh, deactivated and regenerated Ni/Al2O3 catalysts were comprehensively characterized by various techniques. The reduction and redistribution of Ni species as well as the interfacial interaction between Ni nanoparticles and Al2O3 support were investigated in detail. It is found that calcining the deactivated Ni/Al2O3 in air at high temperature can burn out the coke, while the sintered Ni species can combine with superficial Al2O3 to form a surface NiAl2O4 spinel phase through the solid-phase reaction. After the controlled reduction of the NiAl2O4 spinel, highly dispersed Ni nanoparticles on Al2O3 support are re-generated,thus achieving the regeneration of the deactivated Ni/Al2O3. Interestingly, compared with the fresh Ni/Al2O3 catalyst, the sizes of Ni nanoparticles became even smaller in the regenerated ones. The regenerated Ni/Al2O3 showed much enhanced catalytic activity in CO methanation and became more resistant to carbon deposition, due to the better dispersed Ni nanoparticles and strengthened interaction between Ni and Al2O3 support. Our work not only addresses