To investigate the mechanism by which cyclophilin A (CyPA) promotes the progression of atherosclerosis in diabetic rats. Methods: Thirty male Wistar rats were randomly divided into three groups (n=10 each): the control group, the atherosclerosis group (AS group), and the diabetic atherosclerosis group (DM group). After 16 weeks, blood glucose levels, atherosclerotic indices, and inflammatory cytokines were measured in all three groups. Pathological changes in the abdominal aorta were observed using hematoxylin-eosin (HE) staining. The expression of CyPA, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and nuclear factor-kappa B (NF-κB) in the arteries of each group was detected by Western blotting and immunohistochemistry. Results: Over time, the DM group exhibited significant weight loss, elevated blood glucose levels, increased serum inflammatory cytokines, and a markedly higher atherosclerotic index compared to the other groups (all P<0.05). The protein expression of CyPA, p-ERK1/2, and NF-κB in the vascular walls of the DM group was significantly increased (all P<0.05). Conclusion: CyPA protein is highly expressed in the vascular walls of diabetic rats with atherosclerotic lesions, suggesting its potential involvement in the formation and progression of diabetic vascular atherosclerosis.