Depression is a mental illness that seriously harms human health. Therefore, it is crucial to create antidepressant treatments that are effective and powerful. Fetuin-A is a multifunctional glycoprotein mainly released by hepatocytes; it has a complex role in inflammatory processes. We aimed to examine the effect of fetuin-A on lipopolysaccharide-induced depressive like behavior in rats. Forty male albino rats were randomly categorized into four groups; Group I: Control group: (saline + vehicle) for 10 days, Group II: Control treated by fetuin-A group: fetuin-A (100 mg/kg/day) for 10 days, Group III: Depression group: 0.5 mg/kg lipopolysaccharide for 10 days, Group IV: Depression treated with fetuin-A group: Lipopolysaccharide (0.5 mg/kg) for 10 days followed by fetuin-A (100 mg/kg) for 10 days. Behavioral impairments were evaluated. Brain levels of malondialdehyde (MDA) and glutathione peroxidase (GPX) were estimated. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL) IL-6, and brain-derived neurotrophic factor (BDNF), were measured by ELISA. AMPA glutamate receptors (AMPARs GluA1&2), caspase-1 and cAMP response element-binding protein (CREB) mRNA expression by real-time PCR were done. Histopathological assessment of hippocampus was done. Our results revealed that fetuin-A effectively ameliorated LPS-induced behavioral tests impairment through increasing BDNF and CREB. Additionally, fetuin-A treatment caused a decrease in the levels of MDA, TNF-α and IL-6 together with concomitant elevation of GPX and upregulation of caspase-1 and AMPAR GluA1&2 expression. We concluded that fetuin-A ameliorates depression-like behaviors of rats by controlling the Caspase-1/BDNF/CREB Pathway signaling pathway, which may serve as a new target for treatment of depression.