​Herein, we report the synthesis of a new class of functional silver nanoclusters (AgNCs) capped with pillar[5]arene (P5) based host ligands. These NCs are readily prepared via direct synthesis or ligand exchange synthesis and are stable at room temperature for over 4 months. The pillar[5]arene stabilized NCs (Ag29(LA‐P5)12(TPP)2) endorse reversible host‐guest interactions with neutral alkylamines and cationic quaternary ammonium guests. This results into the formation of spherical assemblies with unparalleled changes in their optical properties including an astonishing ≈2000‐fold luminescence enhancement. This is the highest luminescence enhancement ratio reported so far for such atomically precise NCs. Our synthetic protocol paves the way for the preparation of a new generation of metal nanoclusters protected by macrocyclic ligands with molecular recognition and selectivity toward specific guests.