Gynostemma pentaphyllum has been used as traditional medicine for many diseases, including metabolic syndrome (Mets), aging, diabetes, neurodegenerative diseases in China, some East Asian and Southeast Asian countries. It was shown that G. pentaphyllum and gypenosides had anti-obesity and cholesterol-lowering effects too. However, its main active ingredients are still unclear. The objective of this study was to compare the effects of gypenosides before and after heat-processing on high fat obese mice, and to analyze the function of G. pentaphyllum saponin via network pharmacology and molecular docking. The leaves of G. pentaphyllum were heat processed at 120 °C for 3 h to obtain heat-processed G. pentaphyllum. Gypenosides (Gyp) and heat-processed gypenosides (HGyp) were prepared by resin HP-20 chromatography and analyzed using LC-MS from the extracts of G. pentaphyllum before and after heat-processing, respectively. Obesity model was made with high fat diet (HFD). Gyp and HGyp were administrated at 100 mg/kg for 12 weeks in HFD obese mice and the body weight, energy intake, and levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL) were compared. HGyp was administrated at a dose of 50,100,200 mg/kg for 12 weeks in HFD obese mice and the perirenal adipose, epididymal adipose, abdominal adipose, shoulder brown adipose, inguinal adipose were measured. Moreover, the potential targets, hub genes and pathways of damulin A, damulin B, gypenoside L, gypenoside LI for treating Mets were screened out via network pharmacology. According to the results of network pharmacology, core targets of treating Mets were docking with damulin A, gypenoside L, damulin B, gypenoside LI via molecular docking. HGyp showed stronger effects on body weight loss and lipid-lowering in obese mice than Gyp. The contents of gypenoside L, gypenoside LI, damulin A and damulin B of G. pentaphyllum were increased by heat-processing. HGyp significantly decreased the body weight, calorie intake, and levels of TC, TG, LDL, HDL on the obese mice. It up-regulated PPARα and PPARγ in the liver tissues. HGyp reduced significantly the size of adipocytes in inguinal, abdominal, epididymal adipose and increased the proportion of interscapular brown fat. Network pharmacology results showed that 21 potential targets and 12 related-pathways were screened out. HMGCR, ACE, LIPC, LIPG, PPARα PPARδ, PPARγ were the core targets of HGyp against lipid metabolism by molecular docking. The putative functional targets of HGyp may be modulated by AGE-RAGE, TNF, glycerolipid metabolism, lipid and atherosclerosis, cholesterol metabolism, PPAR, fat digestion and absorption, cell adhesion molecules signaling pathway. Gyp and HGyp are valuable for inhibition obesity, lipid-lowering, metabolic regulation. Especially, the effect of HGyp is better than that of Gyp. Display omitted •Gypenosides reduced the body weight, calorie intake, and the contents of TC, TG, LDL of high-fat diet induced mice.•They up-regulated PPARα and PPARγ in the liver tissues.•The targets and pathways of gypenosides on metabolic syndrome were analyzed via network pharmacology and molecular docking.•HMGCR, ACE, LIPC, LIPG, PPARα, PPARδ, PPARγ were the core targets of heat-processed gypenosides against lipid metabolism.•The targets may be modulated by the signaling pathways of AGE-RAGE, glycerolipid metabolism, cholesterol metabolism etc.