The density functional theory (DFT) model ONIOM(M06L/6-311++G(2df,2p):UFF was employed to reveal the catalytic activity of CuII in the paddle-wheel unit of the metal-organic framework (MOF)-505 material in the Mukaiyama aldol reaction compared with the activity of Cu-ZSM-5 zeolites. The aldol reaction between a silyl enol ether and formaldehyde catalyzed by the Lewis acidic site of both materials takes place through a concerted pathway, in which the formation of the CC bond and the transfer of the silyl group occurs in a single step. MOF-505 and Cu-ZSM-5 are predicted to be efficient catalysts for this reaction as they strongly activate the formaldehyde carbonyl carbon electrophile, which leads to a considerably lower reaction barrier compared with the gas-phase system. Both MOF-505 and Cu-ZSM-5 catalysts stabilize the reacting species along the reaction coordinate, thereby lowering the activation energy, compared to the gas-phase system. The activation barriers for the MOF-505, Cu-ZSM-5, and gas-phase system are 48, 21, and 61 kJ mol−1, respectively. Our results show the importance of the enveloping framework by stabilizing the reacting species and promoting the reaction.