Purpose As a formula of traditional Chinese medicine (TCM), Huoxue Jiangtang Decoction (HJD) has positive effects on diabetes mellitus (DM) through improving of the metabolism of glycolipid and the function of β-cell. Hence, this research aims to explore the potential therapeutic effects of HJD on diabetes and reveal its underlying mechanisms. Methods Diabetic rat models induced by high-fat diet (HFD) and streptozotocin (STZ) were included in this study. Following successful modeling, diabetic rats were treated with HJD, and then its therapeutic effects in eight weeks were evaluated. In addition to biochemical indicators, two-bottle preference tests were carried out to examine the rats’ preferences for fat and sugar, and 16S rRNA gene sequencing was performed to disclose the differences of oral microbiota among groups. Finally, Pearson correlation coefficient was used to explore the correlation between oral microbiota and the preferences for fat and sugar. Results It was found that HJD significantly improved the levels of fasting blood glucose (FBG), glucose tolerance, and dyslipidemia. Additionally, HJD contributed to decreasing preferences for fat and sugar in diabetic rats, which plays an important role in food intake. Furthermore, HJD regulated the abundance, distribution, and structure of oral microbiota in diabetic rats, serving as one of the underlying mechanisms of its antidiabetic effects. Conclusion Taken with other formulas, HJD functions to improve the metabolism of glycolipid and the function of β-cell by inhibiting preferences for fat and sugar, as well as regulating the oral microbiota of diabetic rats. Furthermore, a potential correlation between the oral micro-environment and preferences for fat and sugar in STZ-induced diabetic rats is likely to exist.