AbstractTransmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary subunits that modulate AMPA receptor trafficking, gating and pharmacology throughout the brain. Why cornichon‐2 (CNIH‐2), another AMPA receptor‐associated protein, modulates AMPA receptor gating and pharmacology in hippocampal neurons but not cerebellar granule neurons remains unresolved. Here, we report that CNIH‐2 differentially impacts Type‐Ia (γ‐2 or γ‐3) vs. Type‐Ib (γ‐4 or γ‐8) TARP‐containing AMPA receptors. Specifically, with AMPA receptors comprising γ‐2, the cerebellar‐enriched TARP isoform, CNIH‐2 decreasesIKA/IGluratio and decreases cyclothiazide efficacy while having minimal impact on recovery from desensitization and deactivation kinetics. By contrast, with AMPA receptors comprising γ‐8, the hippocampal‐enriched TARP isoform, we find that CNIH‐2 slows deactivation kinetics, increases cyclothiazide potency and occludes a novel AMPA receptor kinetic phenomenon, namely resensitization. Additionally, we find that CNIH‐2 differentially modulates the glutamate off‐kinetics of γ‐8‐containing, but not γ‐2‐containing, AMPA receptors in a manner dependent upon the duration of agonist application. Together, these data demonstrate that the modulation of AMPA receptors by CNIH‐2 depends upon the TARP isoform composition within the receptor complex.