Astragalus membranaceus is a traditional Chinese medicine and has been used for adjuvant clinical therapy for a variety of cancers. However, the mechanism of its action on endometrial carcinoma is unclear. Based on the Gene Expression Omnibus (GEO) database, the Cancer Genome Atlas (TCGA) database, and the Traditional Chinese Medicine System Pharmacology Database (TCMSP™), the drug and target compounds were initially screened to construct a common network module. Twenty active compounds in Astragalus membranaceus were successfully identified, which hit by 463 potential targets related to endometrial cancer. Eight of the more highly predictive compounds (such as Jaranol, Bifendate, Isorhamnetin, Calycosin, 7-O-methylisomucronulatol, Formononetin, Kaempferol, Quercetin) were involved in DNA integrity checkpoint, cyclin-dependent protein kinase holoenzyme complex, and histone kinase activity. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway confirmed that Astragalus membranaceus might play a role in the treatment of endometrial cancer through p53 signalling pathway, transcriptional misregulation in cancer, and endometrial cancer signalling pathway. Drug-target-pathway networks were constructed using Cytoscape to provide a visual perspective. In addition, we verified that formononetin inhibited the proliferation of endometrial cancer cells through cell viability tests and clone formation tests. And qPCR and western blot found that formononetin exerts anti-cancer effects by promoting the expression of estrogen receptor beta (ERβ) and p53. Based on a systematic network pharmacology approach, our works successfully predict the active ingredients and potential targets of Astragalus membranaceus for application to endometrial cancer and helps to illustrate mechanism of action on a comprehensive level.