Objective To explore the mechanism of Gualou Xiebai Baijiu Decoction in improving atherosclerosis (AS) in mice by regulating gut microbiota (GM) and its metabolites. Methous Thirty two male Apoe-/- mice were randomly divided into blank group, model group, atorvastatin(Ato) group and Gualou Xiebai Baijiu Decoction (GXB) group, with 8 mice in each group. Except for the Blank group, three groups of mice were established with AS models and administered by gavage according to their respective groups. Oil red O staining was used to detect the area of aortic plaques. HE staining was used to observe pathological changes in aortic tissue. Using 16S rRNA gene sequencing technology to analyze mouse GM. Detection of mouse GM metabolites trimethylamine oxide (TMAO), short chain fatty acids (SCFA), and serum levels of TG, TC, LDL-C, HDL-C, and NO. Results Compared with the Blank group, both the Model group and Ato group showed an increase in AS plaque area (P<0.05); The serum levels of TG, TC, and LDL-C in the Model group increased (P<0.001), while the levels of HDL-C and NO decreased (P<0.01, P<0.001). Compared with the Model group, the Ato group and GXB group showed a decrease in plaque area (P<0.05); The levels of serum TG, TC, and LDL-C decreased (P<0.001) and the levels of NO were increased (P<0.01) in the Ato and GXB groups; The HDL-C level in the GXB group was increased (P<0.05). Compared with the Ato group, the plaque area in the GXB group was decreased (P<0.05) and the NO level increased (P<0.01).There are 6345 characteristic sequences obtained from 16srRNA. α Diversity analysis suggests that GXB can reduce the richness of GM in AS mice (P<0.001) and improve its uniformity (P<0.05). β Diversity analysis suggests that the microbial community structure of the GXB group is similar to that of the Blank group. There are differences in the abundance of microbial communities among different groups at the phylum and genus levels. At the phylum level, the abundance of Proteobacteria was increased (P<0.01) in mouse AS modeling, while GXB intervention reduced its abundance (P<0.01) and increased the abundance of Verrucomimicrobiota (P<0.05).. At the genus level, GXB intervention can effectively increase the abundance level of Akkermansia (P<0.05). Compared with the Model group, the SCFA level in the GXB group significantly increased (P<0.01), while the TMAO level significantly decreased (P<0.01). Conclusions Gualou Xiebai Baijiu Decoction can regulate intestinal flora and intestinal flora metabolites SCFA, TMAO to improve AS.Akkermansia may be a key bacterial genus for GXB to improve AS through gut microbiota.