Ionotropic glutamate receptors are ligand-gated ion channels found in most excitatory synapses in the brain that allow for rapid information transfer. Due to their quick excitatory processes, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate (AMPA) receptors have been linked to various neurodegenerative disorders, including epilepsy and Parkinson's disease. It has been critical to develop new neuroprotective compounds that inhibit AMPA-sensitive glutamate-controlled channels allosterically, and many classes of AMPA receptor-inhibiting compounds have been synthesized and evaluated. The current study focuses on thirteen 2-oxo-3H-benzoxazole derivatives (COBs) as potential AMPA receptor modulators. The whole-cell patch-clamp technique was used to assess the effects of COBs on AMPA receptor subunits (i.e., GluA1, GluA2, GluA1/2, and GluA2/3) amplitudes in the human embryonic kidney (HEK293) cells and the rates of desensitization and deactivation before and after COBs delivery. According to our findings, the COBs bind AMPA receptors allosterically and alter AMPAR characteristics in various ways. COB-1, COB-2, and COB-13 were the most effective in decreasing AMPAR currents by around 10–12 folds compared to the other COBs. Furthermore, the COBs significantly impacted AMPA receptor deactivation and desensitization rates. Of the examined homomeric and heteromeric AMPAR subunits, GluA2 was the most impacted. COB compounds appear to be a viable candidate for future study and development in regulating neurological diseases involving AMPA receptors.