We applied QM/MM calculations to the asymmetric ring-opening reaction of cyclohexene oxide with aniline catalyzed by a two-dimensional metal-organic framework (MOF) that contains a Cu-paddlewheel (Cu-PDW) unit, aiming to elucidate the reaction mechanism and to identify the factors that determine the enantioselectivity of the reaction. Our QM/MM calculations show that the reaction consists of two major steps. In the first step, ring-opening of the epoxide moiety occurs that leads to an intermediate having an alkoxide ion, and the strong binding of the alkoxide to the Cu(ii) center results in cleavage of one of the four coordination bonds of the copper with carboxylate ligands. In the second step of the reaction, there is a proton transfer from aniline to a distant site-i.e., the alkoxide oxygen atom-to form the β-amino alcohol product, and the carboxylate ligands of the Cu-PDW unit assist this process. The first ring-opening step was calculated as the rate-limiting step, and the enantioselectivity arises from different degrees of CH-π interactions between aniline and a naphthol group in the transition states. The transition state for the ring-opening step in the formation of the (R,R)-isomer is stabilized by CH-π interactions, whereas such interactions are absent in the transition state for the (S,S)-isomer formation. Interestingly, QM/MM calculations also show that the Cu-PDW unit does not maintain a symmetric geometry during the reaction but rather is flexible enough to detach a carboxylate ligand from the copper center, thereby facilitating the reaction. These results illuminate the utility of multiscale QM/MM computations in identifying critical factors determining the reactivity and selectivity of MOF-catalyzed reactions.