Metabolic syndrome (MetS) is associated with osteogenic transdifferentiation of vascular smooth muscle cells (VSMC) and accumulation of arterial calcifications (AC). Metformin (MET) inhibits this transdifferentiation in vitro. Here, we evaluate the in vivo efficacy of oral MET to reduce AC in a model of MetS. 20 young male Wistar rats were divided into 2 groups: one received water, the other water plus 20% fructose to induce MetS. After 14 days, and for another 4 weeks, MET (100 mg/kg/day) was added to half of each group's drinking source, thus: C (water), F (fructose), M (MET) and FM (fructose+MET). Serum and adipose tissue were collected. Aortas were dissected for histomorphometric and immunohistochemical analysis; ex vivo calcification studies; and to isolate VSMC to measure their alkaline phosphatase activity (ALP), collagen production, extracellular mineralization, gene expression of RUNX2 and RAGE (receptor for AGEs), and elastic fiber production. F group showed parameters compatible with MetS. Aortic tunica media from F showed decreased elastic-to-muscular ratio, increased collagen content and increased levels of the AGEs carboxymethyl-lysine. Aortic arches from F presented a tendency for higher ex vivo calcification. VSMC from F showed increased ALP, collagen secretion, mineralization and expression of RUNX2 and RAGE; and decreased elastic fiber production. All these effects were reverted by MET co-treatment (FM group). In vitro, AGEs-BSA upregulated RAGE expression of control VSMC, and this was prevented by MET in an AMPK-dependent manner. Thus, experimental MetS induces RAGE upregulation and osteogenic transdifferentiation of aortic VSMC, that is curbed by oral treatment with MET.