Kang-Xian (KX) pills have been clinically used for the treatment of chronic hepatic injury (CHI). However, the mechanisms of KX on CHI remain unknown. The aim of this study mainly focused on the anti-inflammatory effects of KX in a CHI mouse model based on modulating gut microbiota and gut permeability. We first established a CHI model using carbon tetrachloride (CCl) and treated it with KX. The anti-inflammatory effects of KX on CHI model mice and the changes in gut permeability after KX treatment were also investigated. 16S rRNA analysis was used to study the changes of gut microbiota composition after KX treatment. In addition, gut microbiota was depleted using a combination of antibiotics in order to further confirm that KX could inhibit the inflammatory response and decrease gut permeability to treat CHI by modulating the gut microbiota. Results showed that KX treatment significantly improved liver function in CHI model mice. KX could also increase the levels of tight junction proteins in the colon and decrease the expression of proinflammatory cytokines in the liver. 16S rRNA analysis indicated that KX treatment affected the alpha and beta diversities in CHI model mice. Further analysis of 16S rRNA sequencing indicated that KX treatment increased the ratio of Firmicutes to Bacteroidetes at the phylum level. At the genus level, KX treatment increased the relative abundance of and and decreased the relative abundance of and . However, KX could not alleviate CHI after depleting the gut microbiota. The effects of KX on gut permeability and inflammatory response in the liver were also decreased following the depletion of gut microbiota. In conclusion, our current study demonstrated that gut microbiota was significantly affected during CHI progression. KX could inhibit the inflammatory response and decrease the gut permeability in CHI model mice through modulating the gut microbiota.