<jats:title>Abstract</jats:title> <jats:p>Research on the tissue-protective effects of fluvoxamine (FLV), a selective serotonin reuptake inhibitor, rapidly expands. This study explores FLV’s potential to protect against lipopolysaccharide (LPS)-induced neuroinflammation, a key factor in systemic inflammation-related neuronal damage. Four equal groups of thirty-two female Wistar Albino rats were created: FLV, LPS-FLV (50 mg/kg intraperitoneal), LPS (5 mg/kg intraperitoneal), and control. Both drugs were given in one dose on the same day. Tissues from the brain cortex, cerebellum, and hippocampus were taken for histopathology, immunohistochemistry, biochemistry, and genetic analysis. In the LPS group, histological examinations revealed hyperemia, edema, mild degeneration, neuronal death, and modest gliosis. Additionally, while apelin and total antioxidant status levels were reduced, greater levels of oxidative stress index, glial fibrillary acidic protein (GFAP), mammalian target of rapamycin (mTOR), and total oxidant status were noted. FLV treatment reversed all these findings. Genetic analyses revealed that LPS decreased sirtuin-1 (SIRT-1) and glutathione peroxidase 4 (GPX-4) while increasing high mobility group box protein 1 (HMGB-1). FLV treatment reversed all these parameters, and a significant result was obtained only with GPX-4. In this study, FLV treatment was shown to have anti-inflammatory and neuroprotective effects through various mechanisms on the brain cortex, cerebellum, and hippocampus tissues in addition to its antidepressant effects.</jats:p>