In this work, we report that high catalytic performance of metal–organic frameworks (MOFs) can be obtained through a synergistic effect of postsynthetic modification of MOF nanoparticles and liquid superwetting and confinement in the MOF coating. Specifically, 2-ureido-4[1H]pyrimidinone (UPy) functionalized polysiloxanes were covalently appended onto the UiO-66 nanoparticles via a postsynthetic approach, which were further anchored onto different porous films through multivalent hydrogen bonding of the UPy motifs. The hydrophobic MOF coating can preserve the porosity of the solid substrates, and enable rapid liquid superwetting and confinement within the porous substrates. Using the Knoevenagel condensation as a modeled system, robust and highly catalytic performances of the MOF coating were observed on a range of aldehyde substrates. Gram-scale production of chromene, a pharmaceutical which is typically synthesized via expensive catalysis, was successfully demonstrated on the MOF coating with high yielding rates, demonstrating the great potential of the MOF coating in pharmaceutical synthesis.