An abnormally elevated mortality rate is evident in cases of sepsis. To study specific mechanisms of sepsis experimentally, lipopolysaccharide (LPS) systemically administered has been used as a model, in which an exaggerated immune response, neurochemistry settings, and fever following hypothermia take place. Notably, systemic inflammation (SI) can modulate the central serotonergic pathways and being influenced by it. This influence extends to the hypothalamus, which holds a hierarchical significance in the control of body temperature (Tb). This study investigates the potential impact of orally administered fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) given orally for 7 days before on LPS-induced SI (1.5 mg/kg, i.v.) in rats. The assessment involved monitoring Tb, heat loss index (HLI), along non-shivering thermogenesis assessed by oxygen consumption. Cytokine levels in the spleen and blood, along with nitric oxide (NO), and prostaglandins (PGs) E