BACKGROUND AND PURPOSE The cysteine residue 674 (C674) of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is pivotal in maintaining SERCA2 activity. Substitution of C674 with serine leads to SERCA2 dysfunction and exacerbates atherosclerosis by inducing endoplasmic reticulum stress and inflammation in bone marrow-derived macrophages (BMDMs) and endothelial cells. This study aimed to explore whether SERCA2 dysfunction aggravates atherosclerosis by disrupting fatty acid metabolism and promoting the formation of macrophage foam cells. EXPERIMENTAL APPROACH Heterozygous SERCA2 C674S gene mutation knock-in (SKI) mice were utilized to simulate SERCA2 dysfunction under pathological conditions. Serum from SKI and their littermate wild-type mice were employed for metabolomic testing. The whole aorta and aortic root were isolated for histological analysis. BMDMs were used for protein expression, lipid uptake and accumulation analysis. KEY RESULTS In SKI BMDMs, SERCA2 dysfunction induced the expression of calcineurin (CaN), which promoted nuclear translocation of forkhead box O1 (FoxO1) and transcription of its downstream target fatty acid-binding protein 4 (FABP4), leading to increased fatty acid synthesis and foam cell formation. Inhibition of CaN/FoxO1/FABP4 pathway can correct aberrant lipid metabolism and inhibit the formation of foam cell in SKI BMDMs. Pharmacological interventions targeting FoxO1 or FABP4, or FABP4 partial deficiency significantly ameliorated atherosclerosis progression. CONCLUSIONS AND IMPLICATIONS SERCA2 dysfunction accelerates the progression of atherosclerotic lesions by stimulating CaN/FoxO1/FABP4 pathway, and thus promotes the formation of foam cell. Our finding highlights the importance of SERCA2 function in the context of atherosclerosis and open up a novel therapeutic strategy to combat lipid accumulation and atherosclerosis.