A mixed‐ligand‐based thermo‐chemically robust and undulated metal‐organic framework (MOF) is developed that embraces carboxamide moiety‐grafted porous channels and activation‐induced generation of open‐metal site (OMS). The guest‐free MOF acts as an outstanding heterogeneous catalyst in Hantzsch condensation for electronically assorted substrates with low catalyst loading and short duration under greener conditions than the reported materials. Besides Lewis acidic OMS, the carboxamide group activates the substrate via two‐point hydrogen bonding, highlighting the effectiveness of custom‐made functionalities in this multi‐component reaction. Importantly, the framework demonstrates first ever one‐pot synthesis of 1,4‐dihydropyridine‐based antihypertensive drug foridon, along with four therapeutic molecules ethidine, nifedipine, nemadipine B and Nitrendipine, which are characterized via X‐ray crystallography besides conventional spectroscopic analyses. The integration of redox‐active Co(II) center and acid‐base dual sites benefit the activated MOF catalyzing mild‐condition alcohol oxidation‐Knoevenagel condensation to produce benzylidene malononitriles with wide substrate tolerance and multicyclic performance. For both the multi‐component and atom‐economic reactions, astutely designed control experiments and density functional theory‐based reaction energy profile rationalize synergistic catalysis via pore‐decked antagonistic sites that predominantly transpires inside the MOF channel. This study marks a paradigm shift in sustainable catalysis through task‐specific functionality fuelling, and provides valuable insights on structure‐property synergism at the cutting‐edge MOF design.