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Insulin-like growth factor binding protein 6 (IGFBP6) is thought to be associated with the progression of atherosclerosis (AS). However, whether IGFBP6 is involved in ferroptosis, a key biological process, in the progression of AS remains unclear. In this study, IGFBP6 expression was downregulated in oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs). Overexpression of IGFBP6 inhibited reactive oxygen species (ROS) production, reduced Fe2+ concentration and and inflammatory factor levels, and increased Glutathione (GSH) content in ox-LDL-treated HUVECs. Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, reversed IGFBP6 silencing induced ferroptosis of HUVECs. Mechanistic studies revealed that IGFBP6 is a target of Methyltransferase-like protein 3 (METTL3) that mediates N6-methyladenosine (m6A) modification, and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) recognizes and promotes METTL3-m6A-mediated IGFBP6 mRNA degradation. Downregulated IGFBP6 reduces its protein level by interacting with GPX4, thereby promoting ferroptosis in HUVECs. In addition, APOE-/- mice fed with a high-fat diet were used as an AS animal model, and the results showed that endothelial cell specific METTL3 knockdown or IGFBP6 overexpression hindered the development of AS in mice. In conclusion, knockdown of METTL3 inhibited the degradation of IGFBP6 mRNA in a YTHDF2 dependent manner, thereby inhibiting GPX4-mediated ferroptosis and alleviating AS progression. Insight Box This study provided new molecular targets for the effective treatment of AS. In this study, we constructed an AS cell model and an AS mouse model to explore whether METTL3 affects ferroptosis of HUVECs by regulating IGFBP6 expression through m6A modification through gain of function and loss of function experiments of METTL3 and IGFBP6, thus revealing the molecular mechanism of its involvement in the occurrence and development of AS. Results showed that METTL3 induced GPX4-mediated ferroptosis in HUVECs through m6A-YTHDF2-dependent downregulation of IGFBP6, thereby promoting the progression of AS. These findings suggest that interfering with the METTL3/YTHDF2/IGFBP6/GPX4 axis with small molecules or gene therapy may be a new strategy to intervene the occurrence and development of AS.