Vascular smooth muscle cells (VSMCs) to osteoblast-like cells transdifferentiation induced by high-phosphate is a crucial step in the development of arterial medial calcification (AMC) in patients with chronic kidney disease (CKD), and previous studies implicate Wnt/β-catenin signaling in osteogenic transdifferentiation of VSMCs and AMC. Given that resveratrol's ability to modulate Wnt/β-catenin signaling in other types of cell, we tested the effect of resveratrol on high-phosphate-induced osteogenic transdifferentiation of VSMCs and AMC in CKD. Resveratrol ameliorated AMC in rats with chronic renal failure and calcium deposition in aortic rings and VSMCs cultured in a high-phosphate environment. Resveratrol also diminished high-phosphate-induced osteogenic transdifferentiation of VSMCs in cultured aortic rings and VSMCs. In vitro, resveratrol attenuated the activation of β-catenin induced by high-phosphate and inhibited the expression of Runx2, a downstream effector of Wnt/β-catenin signaling during osteogenic transdifferentiation of VSMCs. Intriguingly, resveratrol inhibited high-phosphate-induced phosphorylation of LRP6 (Ser1490), but didn't inhibit Wnt3a-induced phosphorylation of LRP6 (Ser1490) and Runx2 expression. The expression of several Wnts was induced by high-phosphate, but the expression of Wnt7a, not Wnt2b and Wnt10a could be suppressed by resveratrol. In addition, the expression of both porcupine and wntless, two obligatory proteins for Wnt secretion, was induced by high-phosphate in cultured aortic rings and VSMCs, which could be suppressed by resveratrol. In summary, these findings suggest that resveratrol possesses a vascular protective effect on retarding high-phosphate-induced osteogenic transdifferentiation of VSMCs and AMC in CKD by targeting Wnt/β-catenin signaling, which may, to a large extent, via impeding Wnt secretion.