Background <p>Oxiracetam (ORC) is a commonly used nootropic drug in clinical practice. Alzheimer’s disease (AD) is the primary cause of cognitive decline and loss of independence in the elderly. Currently, the mechanism by which ORC ameliorates AD-related cognitive impairment remains unclear. This study explored its therapeutic potential and underlying mechanisms.</p> Methods <p>Amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic AD model mice and C57BL/6 control mice were utilized, with a comprehensive methodology employed that spanned behavioral assessments, histopathological examinations, molecular biological methods, omics analyses, and electrophysiological evaluations.</p> Results <p>Behavioral tests on APP/PS1 transgenic mice showed that ORC significantly improved cognitive function. HE staining and immunohistochemistry revealed that ORC reduced neurodegeneration in the hippocampal CA1 region of mice. Compared with the wild-type (WT) control group, the concentrations of NeuN, GAP43, MAP2, and Syn proteins in the hippocampus of APP/PS1 mice were significantly decreased, and ORC intervention reversed this decline. Proteomic and transcriptomic analyses suggested that ORC could regulate the glutamate receptor pathway. Electrophysiological studies found that ORC significantly enhanced the reactivity of Hippocampus neurons and increased the frequency and amplitude of sEPSCs, AMPAR-dependent eEPSCs, and mEPSCs. Kinetics studies showed that ORC slowed down the desensitization rate of GluA1 and GluA2 subunits of AMPAR, had no significant effect on their inactivation, and promoted the recovery of GluA2 subunit-desensitized receptors with no effect on GluA1.</p> Conclusions <p>ORC may improve AD-related cognitive impairment through the aforementioned regulation of AMPAR subunit functions, providing theoretical and experimental basis for the analysis of central nervous system drugs and the exploration of new therapeutic targets for AD.</p> Graphical Abstract <p></p>