Aim The key genes for necroptosis in atherosclerosis were screened by bioinformatics methods and verified with the help of in vitro experiments to provide new strategies for the prevention and treatment of atherosclerosis from the perspective of necroptosis. Methods Genes related to atherosclerotic plaques were downloaded from GEO database, and genes related to necroptosis were downloaded from GeneCards database and intersected to obtain atherosclerotic necroptosis genes, and the mechanism of action and signalling pathways of the genes were further analysed by GO and KEGG enrichment analysis, and the protein-protein interaction (PPI) network was constructed and screened for key genes.Finally, macrophages were treated with oxidized low density lipoprotein (ox-LDL) at a final concentration of 100 mg/L, and the expression of key genes was detected by RT-PCR and Western blot. Results A total of 81 atherosclerotic necroptosis genes were obtained. GO and KEGG enrichment analyses revealed that they were mainly enriched in the positive regulation of endopeptidase activity, IκB kinase (IKK)/nuclear factor-κB (NF-κB) signalling, and autophagy signalling pathway. Five key genes including HSPA8, STAT3, HMOX1, SQSTM1 and FAS were obtained by using five computational methods of Cytoscape software cytoHubba plug-in. Compared with the normal control group, the HMOX1 gene was highly expressed in THP-1 macrophages treated with ox-LDL (P＜0.05), while the expression of the HSPA8, STAT3, SQSTM1 and FAS genes showed no significant changes (P＞0.05); the HMOX1 and SQSTM1 genes were highly expressed in RAW264.7 macrophages treated with ox-LDL (P＜0.05), while HSPA8, STAT3 and FAS genes showed no significant changes (P＞0.05). The expression of HMOX1 protein in THP-1 macrophages was also increased. Conclusion HMOX1 may be the key gene of atherosclerotic necroptosis, and it is expected to become a new target for the prevention and treatment of atherosclerosis.