In cooperative catalysis, the combination of chemo- and biocatalysts to perform one-pot reactions is a powerful tool for the improvement of chemical synthesis. Herein, UiO-66-NH2 was employed to stepwise immobilize Pd nanoparticles (NPs) and Candida antarctica lipase B (CalB) for the fabrication of biohybrid catalysts for cascade reactions. Distinct from traditional materials, UiO-66-NH2 has a robust but tunable structure that can be utilized with a ligand exchange approach to adjust its hydrophobicity, resulting in excellent catalyst dispersity in diverse reaction media. These attractive properties contribute to the formation of MOF-based biohybrid catalysts with high activity and selectivity in the synthesis of benzyl hexanoate from benzaldehyde and ethyl hexanoate. With this proof-of-concept, we reasonably expect that future tailor-made MOFs can combine other catalysts, ranging from chemical to biological catalysts for applications in industry.