P2X7 receptor (P2X7R) and NLRP3 cooperatively participate in inflammation and hepatocyte damage during hepatic injury induced by lipopolysaccharides (LPS). High-mobility group box 1 (HMGB1) released from immune cells in response to such stimuli plays a vital role in mediating inflammation via TLR4 and the receptor for advanced glycation end products (RAGE), a receptor for HMGB1. However, the correlation among P2X7R, RAGE and TLR4 in regulating the release of HMGB1 has not been elucidated. Increasing the number of daily foods is found to be beneficial for hepatocyte damage in septic hepatic injury. Hence, we investigated the effects of luteolin, a natural flavonoid mainly existing in vegetables and fruits, on liver injury, focusing on how luteolin participates in hepatitis based on the P2X7R-RAGE-TLR4 axis by regulating the release of HMGB1. The results demonstrated that the indicators of hepatic injury such as increased ALT, AST in the serum and infiltration of immune cells were attenuated after luteolin treatment in LPS-induced mice. Luteolin could also suppress the production and release of HMGB1 and the activation of caspase 1 both in LPS-induced mice and LPS/ATP-stimulated HepG2 cells. Collectively, luteolin reversed LPS-induced hepatic injury, especially inflammation, likely by regulating the release of HMGB1 through the P2X7R-RAGE-TLR4 axis.