Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Rehmanniae Radix Praeparata (RRP) is a popular medicinal herb widely used in traditional Chinese medicine (TCM) to treat CVDs. However, the development of this novel therapeutic product has been stagnant, and its molecular mechanism of action remains unclear. This study aims to explore the effective ingredients of RRP against CVDs, especially atherosclerosis (AS). Using the AutoDock Vina software, the RRP’s ingredients were docked with the targets which can be collected by RCSB and UniProt. Then the screened ingredients and targets could be used to dispose the pathways by the Kyoto Encyclopedia of Genes and Genomes (KEGG). We used GEO, GCBI and DAVID databases to analyze the microarray data of AS which could be used to verify the results of molecular docking, all of which could show the molecular mechanism of RRP on CVDs. We also constructed a compound–target interaction network of CVD with 85 nodes and 272 edges on the basis of molecular docking analysis through Cytoscape. The network showed that forsythiaside, acteoside and stigmasterol are the most important compounds and 2HRR (ACAT (Acyl-CoA cholesterol acyl transferase) protein), 4ATB (MMP13) and 1JBQ (cystathionine beta-synthase) are the most valuable targets in the action of RRP against CVD. We also examined the biological functions involved in the biological process, molecular function and cellular components. In accordance with the analysis of GSE6054 microarray data of AS disease, the 20 most specifically expressed genes (differentially expressed genes [DEGs]) and the top 10 pathways of DEGs were discovered. Five key pathways, including non-alcoholic fatty liver disease (NAFLD), pathways in cancer and PI3K-Akt signalling pathway were also explored. Amongst these pathways, the top three were the pathways in cancer, MAPK signalling pathway and human T-cell lymphotropic virus infection. The pathways in cancer and PI3K-Akt signalling pathway were found simultaneously in the pathway analysis for CVD on RRP and for AS on microarray data. This study provided a new potential herbal medicine against CVD and has increased the understanding on the molecular mechanisms of RRPmediated protection against CVD, especially AS.