The demand for a healthy environment and clean energy has been triggering the study on the preparation of excellent catalysts for the removal of sulfur-containing compounds. In this work, the removal of carbonyl sulfide (COS) from gas streams using Zn/Ni/Al hydrotalcite-derived oxide (HTO) was investigated. In particular, the structure, acid-base properties, and catalytic activity of catalysts prepared under different conditions were measured. A combination of experimental and theoretical methods, including X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), CO2 temperature programmed desorption (TPD), N-2 adsorption-desorption techniques, and density functional theory calculations, were used to elucidate the removal of COS use Zn/Ni/Al HTO. Experimental results indicated that Zn/Ni/Al HTO had relatively high activity for the removal of COS. The density functional theory calculations revealed that "many defects" existed on the Ni3AlO4 (001) plane of crystal, which brought more active centers for the chemical adsorption and hydrolysis of COS. Elemental sulfur, metal sulfide, and sulfate were the final product of COS removal. The consumption of basic sites, as well as the blocking of pores, was considered as the main reason for catalyst deactivation.