The catalytic performance of Cu/ZnO/Al2O3(CuZnAl) catalyst for CO2 hydrogenation to methanol was investigated over a period of 720 h time-on-stream, which showed that the space time yield of CH3OH was decreased by 34.5% during the long-term testing. Different characterization techniques, including X-ray diffraction (XRD), scanning electron microscopy, high resolution transmission electron microscopy, X-ray photoelectron spectroscopy (XPS), and N2O adsorption experiments, were applied to study the deactivation reasons. XRD and N2O adsorption experiments indicated that there were no obvious changes in Cu particle size after the CuZnAl catalyst was exposed to reaction atmosphere for 720 h, while agglomeration took place on ZnO particles. XPS results revealed that part of the metallic Cu was oxidized to Cu2+. The CuZnAl catalyst deactivation was proved to be due to the comprehensive effect of Cu oxidation and ZnO species agglomeration during CO2 hydrogenation to methanol.