Objective: To explore the effect of lidocaine (LID) on ischemia-reperfusion injury in orthotopic liver transplantation (OLT) rats and to analyze its mechanism of action. Methods: 60 rats were randomly divided into control group, model group, low-dose LID group, medium-dose LID group, high-dose LID group, and Verteporfin group, with 10 rats in each group, except for the control group, and other rats were used to construct OLT models. The pathological changes in liver tissue was observed by hematoxylin-eosin (HE) staining, the serum aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin (TBIL) and lactate dehydrogenase (LDH) activities were detected by automatic biochemical analyzer, the liver tissue inflammatory factor tumor necrosis factor-α (TNF-α), interleukin (IL) -6, IL-1β and IL-10 levels were detected by enzyme-linked immunosorbent assay (ELISA), the reactive oxygen species (ROS) was detected by fluorescence probe method, the malondialdehyde (MDA) was detected by thiobarbituric acid colorimetric method, the superoxide dismutase (SOD) was detected by nitrogen blue tetrazole colorimetry, the glutathione peroxidase (GSH-Px) was detected by spectrophotometer method, the apoptosis of liver histiocyte was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) , and the expression of mammalian STE20 like protein kinase (MST1), phosphorylation (p) - MST1, large tumor suppressor factor 1 (LATS1), p-LATS1, Yes associated protein (YAP), p-YAP, as well as apoptosis related proteins B-cell lymphoma 2 (Bcl-2) and Bcl-2 related X protein (Bax) were detected by western blotting (WB). Results: Compared with control group, the liver tissue in model group rats showed injury, liver cells necrosis and a large number of inflammatory cells infiltration, the cell apoptosis rate, serum AST, ALT, TBIL, LDH activity, liver tissue TNF-α, IL-6, IL-1β, MDA, ROS, and Bax levels significantly increased, the liver tissue IL-10, SOD, GSH-Px, Bcl-2, p-MST1/MST1, p-LATS1/LATS1 and p-YAP/YAP proteins expression levels were significantly reduced (P<0.05). Compared with model group, the liver tissue injury was reduced in low-dose LID group, medium-dose LID group, and high-dose LID group, the cell apoptosis rate, serum AST, ALT, TBIL, LDH activity, liver tissue TNF-α, IL-6, IL-1β, MDA, ROS and Bax levels were significantly reduced, the liver tissue IL-10, SOD, GSH-Px, Bcl-2, p-MST1/MST1, p-LATS1/LATS1, and p-YAP/YAP proteins expression levels were significantly increased (P<0.05). Hippo-YAP signaling pathway inhibitor Verteporfin reversed the improvement effect of LID on ischemia-reperfusion injury in OLT rats (P<0.05). Conclusion: LID may activate the Hippo-YAP pathway, which reduce inflammatory response, oxidative stress, and liver cell apoptosis, and improve liver ischemia-reperfusion injury in OLT rats.