Abstract Achieving precise aqueous‐phase modulation of circularly polarized luminescence (CPL) at the molecular level presents significant challenges due to the complex interplay required between chiral organization, emission regulation, and stimuli‐responsive components. Herein, an ultrasensitive pH‐responsive aqueous CPL inversion and amplification system is reported at the molecular scale through positional isomerism‐engineered dynamic host–guest self‐assembly. By synthesizing naphthalene‐bridged bis(phenyl‐vinyl‐pyridinium) positional isomers and coordinating their complexation with carboxylated γ‐cyclodextrin hosts, it is demonstrated that bridge substitution patterns dictate supramolecular chirality through conformation‐specific binding geometries. Unique stoichiometric dependence reveals a ratio‐responsive mechanism mediated by competitive supramolecular interactions with diverse chiroptical behaviors. Capitalizing on the pH‐sensitive carboxyl groups of γ‐cyclodextrin hosts, position‐isomer‐specific chiroptical responses are established within physiologically relevant pH variations between 5 and 6, achieving both 724‐fold circular dichroism amplification and 0.01‐level CPL inversion of dissymmetry factor. This work signifies a supramolecular decoupling strategy that opens a pathway for developing intelligent chiroptical materials, dynamic anti‐counterfeiting systems, and bio‐photonic devices.