In this study, density functional theory calculations have been conducted to explore the size and structural effect of Cu-based catalyst on the hydrogenation of methyl acetate to ethanol. Based on the previous studies that partial hydrogenation of acetyl species is the rate-determining step on Cu-based catalyst, we adopt Cu-13 cluster and the periodic surfaces of Cu (100) and Cu (211) to investigate the adsorption configuration of pivotal species and reaction pathway systematically. It is found that the acetyl hydrogenation is an exothermic reaction on both of Cu-13 cluster and Cu (100) surface, while it is an endothermic reaction on Cu (211) surface. It is also concluded that the energy barrier on Cu (211) surface is lower than that on Cu-13 cluster and Cu (100) surface, which demonstrates the rate-determining step is most likely to take place on Cu (211) surface. The results illustrate that theoretical analyses will provide a helpful evaluation and theoretical assistance for designing possible Cu-based catalysts towards the catalytic reaction in the practical applications.