In this work using first-principles calculations based on spin-polarized density functional theory (DFT), the role of the Cu atom in degrading the poisoning of carbon monoxide (CO) over Ni n Cu clusters is unveiled. The search has been initiated with the examination of structural, magnetic, and electronic properties of Ni n+1 and Ni n Cu clusters (1 ≤ n ≤ 12). X-ray absorption near-edge structure (XANES) spectra of Ni K-edge are computed to extract the information on the oxidation states and coordination environment of metal sites of the clusters. This study is operated with the two forms of dispersion corrections, i.e., D2 and D3, with standard DFT (with LDA and GGA functionals) for the consideration of van der Waals interactions during CO adsorption. The PBE and PBE-D3 approaches are found to be capable of yielding the experimentally observed preferential site for CO adsorption. The effect of spin-polarization on the reactivity of transition metals (TMs) toward CO adsorption is crucially assessed by the electronic reactivity descriptors such as d-band center, d-band width, and fractional filling of d-band using a spin-polarized d-band center model. The effective charge transfer from Cu to Ni atoms makes Ni atoms more efficient of charge and is attributed to the degrading adsorption of CO over Ni n Cu clusters. The Ni12Cu cluster stands out with good CO oxidation activity for the Langmuir–Hinshelwood (L–H) reaction pathway.