The N6-methyladenosine (mA) modification plays an important role in various biological processes, but its role in atherosclerosis remains unknown. The aim of this study was to investigate the role and mechanism of mA modification in endothelial cell inflammation and its influence on atherosclerosis development. We constructed a stable TNF-α-induced endothelial cell inflammation model and assessed the changes in the expression of mA modification-related proteins to identify the major factors involved in this process. The mA-modified mRNAs were identified by methylated RNA immunoprecipitation (RIP) sequencing and forkhead box O1 (FOXO1) was selected as a potential target. Through cytological experiments, we verified whether methyltransferase-like 14 (METTL14) regulates FOXO1 expression by regulating mA-dependent mRNA and protein interaction. The effect of METTL14 on atherosclerosis development was verified using METTL14 knockout mice. These findings confirmed that METTL14 plays major roles in TNF-α-induced endothelial cell inflammation. During endothelial inflammation, mA modification of FOXO1, an important transcription factor, was remarkably increased. Moreover, METTL14 knockdown significantly decreased TNF-α-induced FOXO1 expression. RIP assay confirmed that METTL14 directly binds to FOXO1 mRNA, increases its mA modification, and enhances its translation through subsequent YTH N6-methyladenosine RNA binding protein 1 recognition. Furthermore, METTL14 was shown to interact with FOXO1 and act directly on the promoter regions of and to promote their transcription, thus mediating endothelial cell inflammatory response. experiments showed that METTL14 gene knockout significantly reduced the development of atherosclerotic plaques. METTL14 promotes FOXO1 expression by enhancing its mA modification and inducing endothelial cell inflammatory response as well as atherosclerotic plaque formation. Decreased expression of METTL14 can inhibit endothelial inflammation and atherosclerosis development. Therefore, METTL14 may serve as a potential target for the clinical treatment of atherosclerosis.