Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis, with an unclear pathogenesis and limited treatment options. This study aimed to investigate the therapeutic effects of glutathione (GSH) in a lipopolysaccharide (LPS)-induced sepsis model and to elucidate its underlying mechanism of action. Adult C57BL/6 mice were intraperitoneally injected with LPS (25 mg/kg) to induce sepsis. Prior to LPS administration, GSH (100 mg/kg) was administered intraperitoneally for four consecutive days. Remarkably, GSH treatment significantly reduced mortality in the sepsis model. Behavioral experiments showed notable improvements in locomotor activity in GSH-treated mice, including increased total distance covered and more frequent crossings in the light/dark field test. Additionally, GSH treatment enhanced exploration, as indicated by an increased number of entries into the open arms of the elevated plus maze. In the tail suspension test, GSH treatment reduced resting time and instances of immobility, suggesting potential antidepressant effects. Histological analyses, including Nissl, HE, and immunofluorescence staining, revealed enhanced neuronal survival in the hippocampal CA1 and DG regions following GSH treatment. To explore the molecular mechanisms, Western blot analysis demonstrated that GSH reduced the release of inflammatory markers (IL-1β, IL-6, IL-10) and apoptosis-related proteins (Caspase-3 and cleaved Caspase-3). Furthermore, GSH downregulated PKA, phosphorylated PKA, and NF-κB, suggesting modulation of the PKA and NF-κB signaling pathways. These findings suggest that GSH mitigates neurological damage in sepsis by reducing inflammation and apoptosis, while also improving depressive behavior and cognitive function. GSH may represent a promising therapeutic approach for reducing mortality in SAE.