Vascular calcification (VC) is a major contributor to the progression of cardiovascular disease (CVD). The VC is characterized by arterial stiffness and impaired blood flow. This pathology is especially prevalent in chronic kidney disease (CKD), where dysregulated mineral metabolism and elevated phosphate levels accelerate calcification of vascular smooth muscle cells (VSMCs). Emerging evidence suggests that microRNAs (miRNAs) are key regulators of VC, with the miR-29 family implicated in extracellular matrix remodeling and calcification. We investigated the role of the miR-29a-3p/vascular endothelial growth factor A (Vegfa) axis in CKD-associated VC. Dual-luciferase assays and bioinformatic analysis confirmed that miR-29a-3p directly targets Vegfa, a critical regulator of vascular homeostasis. miR-29a-3p overexpression significantly attenuated VSMC calcification under high phosphate conditions, as indicated by significantly reduced Alizarin Red staining (ARS, P < 0.0001) and intracellular calcium content (ICC, P = 0.0235). Conversely, Vegfa overexpression exacerbated calcification (P = 0.0010 for ICC and P = 0.0001 for ARS). Vegfa knockdown mitigated these effects (P < 0.0001 for both ARS and ICC). Notably, miR-29a-3p counteracted calcification even in Vegfa-overexpressing cells (P < 0.0001 for ARS and P = 0.0235 for ICC), underscoring its protective role in vascular integrity. These findings highlight the therapeutic potential of targeting the miR-29a-3p/Vegfa axis for VC management in patients with CKD. miRNA-based interventions may offer a promising strategy for preventing pathological calcification and reducing the risk of CVD in affected patients.