There is experimental evidence that the actual active phase of the Ni2P catalyst under hydrodesulfurization (HDS) reaction conditions is a nickel phosphosulfide phase formed on the catalyst surface. Combining DFT calculations and an atomistic thermodynamic approach, we investigated the possibility of sulfur adsorption as well as the replacement of surface phosphorus by sulfur on the (0001) and (100) surfaces of the Ni2P catalyst. Our DFT calculations showed that sulfur could replace up to 100% of the surface phosphorus under hydrodesulfurization (HDS) reaction conditions. We identify that possible sulfur adsorption sites on both surface terminations are arrangements of Ni trimers (Ni3 sites). We found that only the phosphosulfide phase formed on the (100)-AB_Ni2P surface termination has coordinatively unsaturated Ni atoms available for the adsorption of organic sulfur-containing compounds. Our results suggest that the phosphosulfide phase formed on the (100)-AB_Ni2P termination and not on the (0001)-Ni3P2 termination could be responsible for the high HDS activity of the Ni2P catalyst. Upon the replacement of P by S, the Ni3 sites undergo tensile strain, and their reactivity toward S adsorption is modified by the imposed strain. We found that the Ni–Ni bond distance is an important parameter in describing the HDS activity of the Ni2P catalyst. By analyzing the relationship among the ensemble, ligand, and strain effects, we were able to provide a better understanding of the promoting effect introduced by the formation of the nickel phosphosulfide phase.