Dysregulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors underlies a variety of neurological conditions, including epilepsy and neurodegenerative disorders. Pharmacological approaches that selectively modulate AMPA receptor subunits offer significant promise in mitigating glutamate-mediated excitotoxicity. We investigated eight newly synthesized coumarin–benzodiazepine (CD) hybrid derivatives designed as negative allosteric modulators of AMPA receptors, seeking both potency and selectivity. Using whole-cell patch-clamp electrophysiology in HEK293 cells expressing specific AMPA receptor subunits (GluA1–4), we evaluated the ability of each compound to alter receptor kinetics, particularly desensitization and deactivation. Among the tested derivatives, one molecule (CD8) exhibited a notably high affinity for AMPA receptors, with potent inhibition observed across multiple subunit combinations. Crucially, CD8 displayed minimal off-target activity against kainate and NMDA receptors, underscoring its selectivity for AMPA receptor subtypes. Structurally, CD8’s carboxyl substituent at the para position of the phenyl ring emerged as pivotal for enhanced receptor binding and negative modulation. Furthermore, kinetics analyses revealed that certain derivatives, including CD8, not only attenuated peak current amplitude but also accelerated deactivation rates and reduced desensitization—indicative of a robust negative allosteric mechanism distinct from the orthosteric glutamate-binding site. Taken together, these findings highlight the potential of coumarin–benzodiazepine hybrids as selective modulators of AMPA receptors. By dampening hyperexcitatory neuronal signaling through targeted receptor inhibition, these derivatives hold promise as a therapeutic avenue for a range of central nervous system pathologies. Future research will probe how these compounds interact with auxiliary proteins (e.g., TARPs) to further optimize AMPA receptor gating in native neuronal environments, thereby refining their translational potential for neurological conditions associated with abnormal glutamatergic transmission.