Objective To explore the efficacy of Si-jun-zi Decoction in treating alcoholic liver disease and its mechanism. Methods Male C57BL/6 mice were randomly divided into normal group (group A), alcohol model group (group B), low-dose Si-jun-zi Decoction group (group C), and high-dose Si-jun-zi Decoction group (group D). Mice in the groups B-D were intragastrically administered ethanol solution (6 g/kg) with a volume fraction of 0.56 per day, while mice in group A were intragastrically administered an equal dose of normal saline per day. Meanwhile, mice in groups C and D were given Si-jun-zi Decoction at 5 and 10 g/kg per day, respectively. The body mass was measured once every 5 d. The experiment lasted for 18 d. After gavage, fresh feces were collected to analyze the changes in intestinal flora by 16S rDNA gene sequencing. After anesthesia, blood was collected from the canthus, and serum was collected for intestinal permeability test. Blood, liver, and spleen tissues were collected. The liver and spleen indices as well as the content of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (T-BIL), alkaline phosphatase (ALP), triglyceride (TG), and total cholesterol (TC) were measured in each group. The morphological changes of liver and spleen were observed in each group using hematoxylin-eosin and oil red O staining. Results Compared with group B, group D had significantly different body mass and liver and spleen indices (t=3.53-4.41,P