Objective Vascular calcification leads to increased cardiovascular morbidity and mortality and prevalent in patients with chronic kidney disease. Although several reports have implicated mitochondrial dysfunction in cardiovascular disease and chronic kidney disease, little is known about the potential role of mitochondrial dysfunction in the process of vascular calcification. Methods The present study investigated the effect of alpha-lipoic acid (ALA), a naturally occurring antioxidant that improves mitochondrial function, on vascular calcification in vitro and in vivo. Calcifying vascular smooth muscle cells (VSMCs) treated with inorganic phosphate (Pi) exhibited mitochondrial dysfunction, as evidenced by decreased mitochondrial membrane potential and ATP production, the disruption of mitochondrial structural integrity, and concurrently increased production of reactive oxygen species. Results Pi-induced functional and structural mitochondrial defects were accompanied by mitochondria-dependent apoptotic events, including release of cytochrome c from the mitochondria into the cytosol, subsequent activation of caspase-9 and -3, and chromosomal DNA fragmentation. ALA blocked the Pi-induced VSMC apoptosis and calcification by recovery of mitochondrial function and intracellular redox status. Moreover, ALA inhibited Pi-induced downregulation of cell survival signals through the binding of growth arrest-specific gene 6 (Gas6) to its cognate receptor Axl and subsequent Akt activation, resulting in increased survival and decreased apoptosis. ALA significantly ameliorated vitamin D3-induced aortic calcification and mitochondrial damage in mice. Conclusion The findings suggest ALA attenuates vascular calcification by inhibiting VSMC apoptosis through two distinct mechanisms; restoration of the Gas6/Axl/Akt survival pathway and preservation of mitochondrial function via its antioxidant potential.