Objective To investigate the protective effect of 4-phenylbutyric acid (PBA) on liver injury induced by severe acute pancreatitis (SAP) in rats and its possible mechanism. Methods Twenty-four SPF adult male Sprague Dawley rats were randomly divided into three groups: shame operation group (SO group,n=8), SAP group (n=8), and PBA group (n=8). SAP model was induced by retrograde injection of 5% sodium taurocholate (1 mL/kg) in biliopancreatic duct in SAP group and PBA group. PBA solution (50 mg/kg) was administeredvia intraperitoneal injection for 3 days prior to establishing models in PBA group. Rats were injected equivalent saline solution instead of PBA solution in SAP group and SO group. All rats were sacrificed at 12 h after modeling. Blood samples were collected by inferior vena cava puncture, and serum levels of amylase (AMY), alanine aminotransferase (ALT), and aspartate transaminase (AST) were measured using a fully automatic chemistry analyzer. The head of pancreas and right lobe of hepatic tissues were harvested and pathological examination was observed under the light microscope. Expressions of glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and Caspase-3 in hepatic tissues were evaluated by immunohistochemistry assay. Results Compared with SO group, the serum levels of AMY, ALT and AST were significantly increased in SAP group (P＜0.05). The serum levels of ALT and AST in PBA group were significantly lower than those in SAP group (P＜0.05). There was no difference of the serum levels of AMY between in PBA group and SAP group (P＞0.05). Compared with SO group, the damages of the pancreas and liver tissues and the expressions of GRP78, CHOP and Caspase-3 in hepatic tissues were significantly increased in SAP group (P＜0.05). And the above indices in PBA group were significantly decreased when compared with SAP group. Conclusions PBA can alleviate severe acute pancreatitis-induced liver injury, and the mechanism may be associated with inhibition of endoplasmic reticulum stress (ERS) and reduction of hepatocyte apoptosis.