Inflammation is an important biological event in host defenses against bacterial or viral infections. However, excessive inflammatory responses by aberrantly activated macrophages, producing   excess amounts of inflammatory mediators, which disrupt immune homeostasis and result in immunopathological conditions such as sepsis. Sepsis was recognized as a systemic inflammatory response syndrome after serious infections, most commonly with bacteria, which have a high mortality rate. Propolis (Prop) could be used as adjuvant therapy in the management of sepsis. The present study aimed to investigate the protective effect of Prop against sepsis-induced in rats. Evaluation of complete blood count, activity of liver function enzymes in serum; alanine and aspartate aminotransferases were recorded.  Oxidant/antioxidant markers in liver tissue namely; malonaldehyde, nitrites/nitrates, glutathione disulfide, glutathione levels, catalase and superoxide dismutase activities. Also, tumor necrosis factor-alpha and prostaglandin E-2 levels in both serum and liver tissue were estimated.   Furthermore, interleukin-8, cyclooxygenase-2 and inducible nitric oxide synthase genes expression were determined. Histopathological examination of liver tissue was investigated. Brain neurotransmitters; Dopamine, Norepinephrine and 5-hydroxytryptamine were also determined against sepsis-induced inflammation. The present study indicated that Prop could be an efficient protector that resets sepsis-induced severe oxidative stress, inflammation and improve the immune response of the liver as well as septic neurotoxic problems.