Catalytic hydrodeoxygenation is of prime importance in the valorization of biomass-based feedstocks to produce essential chemicals and fuels. To carry out this process in a more cost-effective and sustainable manner, the use of 3D-metal-based nanostructured catalysts is highly desired. Here, we report the preparation and application of Ni nanoparticles supported on ZSM-5 (the Si/Al ratio is 80) as a general and efficient hydrodeoxygenation catalyst. These Ni-based nanoparticles catalyze the selective hydrodeoxygenation of a wide range of funcational substrates, including ketones, ethers, and phenols, and also reduce aromatic rings to produce (cyclo) alkanes. Notably, the hydrodeoxygenation of fatty acid derived ketones to long-chain alkanes, lignin derived molecules, and polyether ether ketone decomposition compounds to cyclohexane-based products highlight the versatility of this novel Ni catalyst.