Objective To explore the mechanism of Gualou Xiebai Baijiu Decoction ( GXB) in improving atherosclerosis (AS) in mice by regulating the gut microbiota ( GM) and its metabolites. Methods Thirty-two male ApoE^{- / -} mice were divided randomly into a Blank group, Model group, atorvastatin (Ato) group, and GXB group (n= 8mice per group). AS was established in all mice, except the Blank group, and the respective treatments were administered by gavage. Aortic plaques were detected by Oil red O staining and pathological changes in aortic tissue were detected by hematoxylin and eosin staining. The GM was analyzed using 16S rRNA gene sequencing technology, and mouse GM metabolites, including trimethylamine oxide (TMAO), short-chain fatty acids ( SCFA), and serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDLC), and nitric oxide (NO) were determined. Results Compared with the Blank group, mice in the Model and Ato groups showed an increase in AS plaque area (P<0. 05). Serum levels of TG, TC, and LDL-C were increased (P<0. 001) while levels of HDL-C and NO were decreased (P<0. 01, P<0. 001) in the Model group compared with the Blank group. The plaque area was decreased (P<0. 05), serum levels of TG, TC, and LDL-C were decreased (P<0. 001), and NO levels were increased (P<0. 01) in the Ato and GXB groups, while HDL-C levels were increased in the GXB group (P<0. 05) compared with the Model group. Plaque area was decreased (P<0. 05) and the NO level was increased (P<0. 01) in the GXB group compared with the Ato group. A total of 6345 characteristic sequences were obtained from 16S rRNA analysis.α-Diversity analysis indicated that GXB reduced the richness of the GM in AS mice ( P < 0. 001) and improved its uniformity (P<0. 05). β-Diversity analysis suggested that the microbial community structure in the GXB group was similar to that in the Blank group. The abundance of microbial communities differed among the groups at the phylum and genus levels. At the phylum level, the abundance of Proteobacteria was increased (P<0. 01) in AS mice, while GXB intervention reduced the abundance of Proteobacteria (P<0. 01) and increased the abundance of Verrucomimicrobiota (P<0. 05). At the genus level, GXB effectively increased the abundance of Akkermansia (P<0. 05). SCFAs were significantly increased (P<0. 01) and TMAO levels were significantly decreased (P<0. 01) in the GXB group compared with the Model group. Conclusions GXB can regulate the intestinal flora and intestinal flora metabolites SCFA and TMAO to improve AS.Akkermansia may be a key bacterial genus of the gut microbiota through which GXB may improve AS.