The transformation of nickel (Ni) porphyrins in hydrodemetallization (HDM) was investigated using 2,3,7,8,12,13,17,18-nickel-octaethylporphine (Ni-OEP) as the model compound, which was dissolved in a white oil. The HDM reactions were carried out in a high-pressure trickle-bed reactor over the oxidic and sulfided NiMo/Al2O3 catalyst. The molecular formulas of Ni compounds in the feed and hydrotreated products were characterized by positive-ion electrospray ionization (+ESI) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). The hydrotreated products were separated into two subfractions by silica gel chromatography. Molecular structures of Ni-containing intermediates were investigated by ultraviolet visible (UV-vis) spectrometry, hydrogen nuclear magnetic resonance (H-1 NMR), and density function theory (DFT) calculations. The major Ni-containing intermediates of Ni-OEP were dihydrogenated (Ni-OEPH2) and tetrahydrogenated (Ni-OEPH4) porphyrins during the hydrotreating. The structure of Ni-OEPH2 was speculated as 1,2-dihydro-Ni-OEPH2, which could be further hydrogenated into Ni-OEPH4. Ni-OEPH4 was first detected in the Ni-OEP hydrotreated products, which should be much more unstable than Ni-OEPH2 and could be easily demetallized. The main pathway of Ni-OEP conversion during the hydrotreating was the hydrodemetallization route, and Ni was removed with the porphyrin ring rapid fragmentation. The results indicate that the catalyst with high hydrogenation and hydrogenolysis activities on hydrocarbons as well as sulfur and nitrogen compounds could have a high activity on the HDM of Ni porphyrins.