Dynamic combinatorial chemistry (DCC) offers a powerful yet underutilized strategy for ligand discovery, largely limited by heterogeneous kinetic constraints in exchange reactions and analytical challenges. Here we report a peptide nucleic acid (PNA)‐templated trivalent DCC platform that enables rapid, target‐guided exploration of 125 000 assemblies to identify ultrahigh‐affinity and reversible thrombin inhibitors. Short hybridization handles allow unbiased equilibration of a three‐fragment library, and size‐exclusion filtration combined with matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) provides a complete selection–readout cycle in under 1 h. From this library, thrombin amplifies synergistic fragment combinations engaging the active site and both exosites, yielding a trivalent inhibitor with apparent sub‐picomolar affinity ( K _D ≈ 84 fM) and near‐stoichiometric inhibition. Despite its extreme potency, inhibition remains fully reversible: addition of a single‐stranded toehold antidote rapidly disassembles the complex and restores activity in buffer and in plasma. These results establish hybridization‐guided DCC as a fast, scalable route to programmable multivalent therapeutics with on‐demand reversibility.