<p>Obesity has become a global public problem. Guizhi Fuling Decoction (GZFLD) is a traditional Chinese medicine decoction. This study aims to investigate the therapeutic effects of GZFLD on high-fat diet (HFD)-induced obesity in mice. The obese mouse model was induced by HFD. The effects of GZFLD on obesity were assessed by recording body weight (BW) and inguinal white adipose tissue (Ing-WAT) weight of mice. Histological changes in adipose and liver tissues were evaluated by hematoxylin–eosin staining. Enzyme-linked immunosorbent assay was exploited to detect the expression of blood lipid indexes and inflammatory factors. The expression of pyroptosis-related proteins was detected by western blot and immunohistochemistry. Transcriptome sequencing was executed to explore the mechanism of GZFLD on obese mice and screen the pyroptosis-related genes. Furthermore, the effect of Angiotensin-converting enzyme 2 (ACE2) on obese mice was verified by ACE2 inhibitor-DX600. In HFD-induced mice, with the increased dose of GZFLD, GZFLD significantly improved obesity, hepatic steatosis and dyslipidemia, with decreased BW, Ing-WAT weight, Ing-WAT/BW ratio, levels of triglycerides, cholesterol low-density lipoprotein, and increased high-density lipoprotein levels. Hematoxylin–eosin staining exhibited that GZFLD improved steatosis and adipocyte enlargement induced by HFD. Additionally, GZFLD suppressed the levels of lactate dehydrogenase, inflammation factors, and pyroptosis-related proteins. RNA-sequencing identified ACE2 as a key gene target. The ACE2 inhibitor DX600 attenuated the inhibitory effects of GZFLD on hepatic steatosis, dyslipidemia, inflammation, and pyroptosis in HFD-induced obese mice. Collectively, GZFLD had a protective effect on HFD-induced obesity by alleviating dyslipidemia, and inhibiting inflammation and pyroptosis, which was achieved by up-regulating ACE2.</p>