Abstract Previous studies have established a possible link between hyperhomocysteinemia (HHcy) and dyslipidemia. Circular RNAs (circRNAs) play important regulatory roles in the development of atherosclerosis. However, the biological functions and potential molecular mechanisms of circRNAs in HHcy‐induced lipid accumulation leading to atherosclerosis are still unclear. In this study, it is determined that homocysteine (Hcy) downregulates the expression of circ‐PIAS1‐5 by global circRNA expression profiling and that circ‐PIAS1‐5 inhibits Hcy‐mediated lipid accumulation in foam cells and the pathogenesis of atherosclerosis by acting as a sponge for miR‐219a‐2‐3p. Circ‐PIAS1‐5 is identified as a potential diagnostic biomarker of HHcy‐associated atherosclerosis in male “apolipoprotein E knockout (ApoE−/−)” mice. Mechanistically, circ‐PIAS1‐5 activates the adenosine 5‘‐monophosphate (AMP)‐activated protein kinase pathway by regulating TEAD1 through miR‐219a‐2‐3p, and Hcy mediates the m6A modification and nuclear export of circ‐PIAS1‐5 via YTHDC1 to increase lipid accumulation in foam cells and accelerate the pathogenesis of atherosclerosis. Taken together, these results highlight the role of circ‐PIAS1‐5 in the Hcy‐mediated pathogenesis of atherosclerosis and suggest its potential application as a prognostic biomarker of atherosclerosis induced by HHcy.