Aim To predict the anti-atherosclerotic targets and signal pathways of Morinda officinalis by using traditional Chinese medicine system pharmacology, small molecule drug target prediction and disease genome database, and combined with the molecular docking technology. Methods The technology platform of Chinese medicine system pharmacology (TCMSP) and the online platform for small molecule drug target prediction (Swiss Target Prediction) were used to explore the active components of Morinda officinalis and the targets of its response. GeneCards, OMIM, Disgenet and UniProt were used to collect and screen the disease targets related to atherosclerosis. The intersection genes were obtained and imported into the String 11.5 database to construct the disease-drug protein-protein interaction (String-PPI) network map. Cytoscape 3.9.1 software was used to visualize key target networks. Then, GO and KEGG enrichment were performed using Metascape online platform to explore the molecular targets of anti-atherosclerosis, the pathway map was drawn through KEGG database. Finally, Autodock vina 1.1.2 software was used to verify the molecular docking of core compounds and target genes of Morinda officinalis. Results A total of 17 effective drug compounds including β-sitosterol and anthraquinone, 73 core targets and 1 450 key disease genes were collected from the above databases, then 35 core genes of Morinda officinalis acted on atherosclerosis were obtained after the intersection. 32 genes including SRC, PGTS2, TGFβ1, REN, ESR1 and CASP3, were identified by String-PPI. KEGG enriched 75 signaling pathways, involving lipid-atherosclerosis, advanced glycosylation end products and receptors and PI3K-Akt signaling pathway, among which lipid-atherosclerosis pathway mainly involves six target genes such as SRC, BCL2, BAX, CASP3, GSK3B and RXRA. Molecular docking showed that the main chemical components of Morinda officinalis had strong binding activity with core genes. Conclusion Morinda officinalis can regulate the expression of 32 major genes including SRC, PGTS2, TGFβ1, REN, RXRA,ESR1, CASP3 through β-sitosterol, anthraquinone and other major chemical components, controls vascular endothelial inflammation and inhibits cell proliferation, migration and apoptosis, therefore plays the certain role of anti-atherosclerosis.