Objective To investigate the effect of restraint stress on liver injury in mice induced by D-galactosamine and lipopolysaccharide (D+L).Methods Normal BALB/c (B/c) mice were randomly divided into normal control, stress control, D+L group, and D+L+stress group. The mice of normal control group were bred routinely. The stress group was given stress regularly and quantitatively. Mice in the D+L group were injected intraperitoneally with mixed solution of D-galactosamine and lipopolysaccharide at final concentration of 30 mg/mL and 2 μg/mL, respectively, once every two days. The D+L+stress group was given equal stress as stress group after injection of D-galactosamine and lipopolysaccharide mixed solution. Eight weeks later, blood samples were collected to test serum aminotransferase (ALT) and aspartate aminotransferase (AST), liver tissue samples from all animals were collected to evaluate the degree of liver fibrosis by HE and Masson staining. Results At the 8^th week, the ALT and AST values in the D+L+stress group were significantly reduced(P<0.01)and AST/ALT value was significantly increased(P<0.01)compared with that in the D+L group. For HE and Masson staining, disordered structure of hepatic lobules, nodular hyperplasia, and necrosis of epithelial cells were present in animals of the D+L group. However, no obvious pathological changes were observewd in the D+L+stress group. For fibrosis scores, the fibrosis grade in the D+L+stress group was significantly decreased than that of the D+L group (P<0.05). Conclusions Constraint stress presents protective effect on D-galactosamine and lipopolysaccharide induced liver injury in mice.