Recent studies have shown that liver dysfunction is an early event in sepsis. Pre-existing liver dysfunction is a risk factor for progression of infection to sepsis. However, the mechanism of the liver immune response in promoting sepsis and the importance of liver function are not completely understood. In the present study, we investigated the protective effect of erythropoietin (EPO) against mitochondrial dysfunction in a lipopolysaccharide (LPS)-induced sepsis model, and examined the underlying signaling mechanisms. Enzyme linked immunosorbent assay (ELISA) and reactive oxygen species (ROS) analysis were used to evaluate the levels of interleukin (IL)-1β and ROS. The effects of EPO on hepatic mitochondrial function were studied by detecting the mitochondrial DNA (mtDNA) copy number using real-time PCR (RT-PCR). To explore the mechanism of action of EPO in sepsis, protein expressions of IL-1β, caspase-1 and NLRP3 were assessed by Western blotting; liver histopathology and ultrastructure of liver mitochondria was examined by transmission electron microscopy. We found that LPS treatment increased serum IL-1β and ROS levels, the effect of which was attenuated by EPO. Moreover, LPS treatment also increased the mtDNA copy number and the protein expressions of IL-11β, caspase-1, and NLRP3, which were suppressed by EPO. Histological examination of liver showed LPS-induced cellular edema in hepatic lobules, lymphocytic infiltration and hepatocellular necrosis; these changes were also alleviated by EPO treatment. On electron microscopy, the size of hepatocellular mitochondria in the LPS group was smaller than that in the control group, and the changes were reversed by EPO in the LPS+EPO group. Our results suggest that EPO alleviated liver and mitochondrial damage induced by LPS, possibly via inhibition of NLRP3 signaling.