Objective To explore the molecular mechanism of a classic traditional Chinese medicine compatibility combination of Astragalus membranaceus (A.m) and Angelica sinensis (A.s) in treatment of diabetes mellitus with cardiovascular complications. Methods The BATMAN database was used to analyze A.m and A.s respectively. The chips data related to diabetes mellitus with cardiovascular complications were retrieved from GEO database. The differential genes were analyzed by GEO2R to construct the protein-protein interaction (PPI) network, and the key target genes of A.m-A.s were obtained by topology, and DAVID database was used for gene ontology (GO) and KEGG pathway enrichment analysis of key genes. A total of 20 SD rats were randomly divided into healthy control group, diabetes mellitus complicated with cardiovascular complications group, metformin group, and A.m-A.s group (5 each). All the rats except those in HC group were fed with high fat and high sugar feeds, and used to establish the model of diabetes mellitus with cardiovascular complications. The expressions of PI3K and Akt3 in cardiomyocytes of the rats in each group were observed. Results (1) A total of 1332 target genes related to A.m-A.s combination were analysis obtained from BATMAN database, and 3 chip data files related to diabetes with cardiovascular diseases (GSE26887, GSE43950 and GSE46262)were retrieved from GEO database including 2759 differential genes screened by GEO2R analysis and 247 key genes of A.m-A.s combination in treatment of diabetes mellitus with cardiovascular complications. (2) The protein-protein interaction (PPI) network diagram of key targets was constructed by STRING database, and the "A.m-A.s- active ingredients-targets" network was constructed by Cytoscape 3.7.2. The functional enrichment analysis with DAVID database showed that the biological process of A.m-A.s in treatment of diabetes mellitus and cardiovascular complications was mainly concentrated in positive and negative regulation of RNA polymerase II promoter transcription, redox process, signal transduction, apoptosis process, inflammatory reaction, and positive regulation of cell proliferation, etc. The signaling pathways mainly include metabolic pathway, cancer pathway, TNF signaling pathway, cAMP signaling pathway, cGMP-PKG signaling pathway, PI3K-Akt signaling pathway, non-alcoholic fatty liver disease pathway, and insulin resistance pathway and so on. (3) The animal model experiment with SD rats in vivo of A.m-A.s combination in treatment of diabetes mellitus with cardiovascular complications suggested that, compared with healthy control group, the expressions of PI3K and Akt3 decreased in cardiomyocytes of the untreated model group, and the difference was statistically significant (P<0.05, P<0.01); the expressions of PI3K in the treatment groups were higher than that in the model group, but lower than that in the healthy control group, and the difference was statistically significant (P<0.01). Conclusion The characteristics of A.m-A.s combination in treatment of diabetes mellitus with cardiovascular complications are "multi-components, multi-targets and multi-pathways", and multiple key genes and signal pathways can play important roles. Further research is expected to broaden the ideas of diagnosis and treatments of diabetes with traditional Chinese medicine.