Aim To investigate the role and mechanism of RNA binding protein zinc finger protein 36 (ZFP36) in vascular calcification. Methods Human aortic smooth muscle cells were infected with ZFP36-overexpressing virus or transfected with ZFP36 siRNA, followed by high phosphate stimulation to observe the effect of overexpression or knockdown of ZFP36 on smooth muscle cell calcification; RNA immunoprecipitation and stability experiments were used to detect whether Runx2 was the target gene of ZFP36; Smooth muscle specific ZFP36 knockout mice were generated and vitamin D was used to induce vascular calcification. Alizarin Red and Von Kossa staining were used to observe calcification of aortic vessels, and Western blot was used to detect Runx2 protein expression.Results ZFP36 expression was elevated under calcification-stimulating conditions. Overexpression of ZFP36 alleviated high phosphate-induced smooth muscle cell calcification, while knockdown of ZFP36 exacerbated calcification. ZFP36 could bind to Runx2 mRNA and promote its degradation. At the cellular level, ZFP36 could inhibit smooth muscle cell calcification via Runx2. At the animal level, knockout of ZFP36 in smooth muscle exacerbated vascular calcification induced by vitamin D. Conclusion ZFP36 inhibits vascular calcification by targeting Runx2 mRNA and suppressing its expression in smooth muscle cells.