By synergizing the advantages of homogeneous and heterogeneous catalysis, single-site heterogeneous catalysis represents a highly promising opportunity for many catalytic processes. Particularly, the unprecedented designability and versatility of metal-organic frameworks (MOFs) promote them as salient platforms for designing single-site catalytic materials by introducing isolated, well-defined active sites into the frameworks. Herein, we design new MOF-supported single-site catalysts for CO hydrogenation to methanol (CHOH), a reaction of great significance in CO valorization. Specifically, N-heterocyclic carbene (NHC), a class of excellent modifiers and anchors, is used to anchor coinage metal hydrides M(I)-H (M = Cu, Ag, and Au) onto the organic linker of UiO-68. The strong metal-ligand interactions between NHC and M(I)-H verify the robustness and feasibility of our design strategy. On the tailor-made catalysts, a three-stage sequential transformation is proposed for CHOH synthesis with HCOOH and HCHO as the transit intermediates. A density functional theory-based comparative study suggests that UiO-68 decorated with NHC-Cu(I)-H performs best for CO hydrogenation to HCOOH. This is further rationalized by three linear relationships for the Gibbs energy barrier of CO hydrogenation to HCOO intermediate, the first with the NBO charge of the hydride in NHC-M(I)-H, the second with the electronegativity of M, and the third with the gap between the lowest unoccupied molecular orbital of CO and the highest occupied molecular orbital of the catalyst. It is confirmed that the high efficiency of MOF-supported NHC-Cu(I)-H for CO transformation to CHOH is via the proposed three-stage mechanism, and in each stage, the step involving heterolytic dissociation of H together with product generation is the most energy-intensive. The rate-limiting step in the entire mechanism is identified to be H dissociation accompanying with simultaneous HCHO and HO formation. Altogether, the tailor-made UiO-68 decorated with NHC-Cu(I)-H features well-defined active sites, enables precise manipulation of reaction paths, and demonstrates excellent reactivity for CO hydrogenation to CHOH. It is also predicted to surpass a recently reported MOF-808 catalyst consisting of neighboring Zn-O-Zr sites. The designed MOFs as well as the proposed strategy here establish a new paradigm and can be extended to other hydrogenation reactions.