Hyperhomocysteine has become a critical risk for atherosclerosis and can stimulate proliferation and migration of vascular smooth muscle cells (VSMCs). N‐methyl‐D‐aspartic acid receptor (NMDAR) is a receptor of homocysteine and mediates the effects of homocysteine on VSMCs. Bioinformatics analysis has shown NMDAR is a potential target of microRNA‐217 (miR‐217), which exerts multiple functions in cancer tumorigenesis and carotid plaque progression. In this study, we sought to investigate the role of miR‐217 in VSMCs phenotype transition under homocysteine exposure and elucidate its effect on atherosclerotic plaque formation. After treating with several doses of homocysteine (0–8 × 10−4 mol/L) for 24 hours, the expression of miR‐217 in HA‐VSMCs and rat aortic VSMCs was not altered. Intriguingly, the expression of NMDAR mRNA and protein was reduced by homocysteine in a dose‐dependent manner. Transfection of miR‐217 mimic significantly inhibited the proliferation and migration of VSMCs with homocysteine treatment, while transfection of miR‐217 inhibitor promoted VSMCs migration. Moreover, miR‐217 mimic down‐regulated while miR‐217 inhibitor up‐regulated NMDAR protein expression but not NMDAR mRNA expression. Through luciferase reporter assay, we showed that miR‐217 could directly bind to the 3′‐UTR of NMDAR. MiR‐217 mimic transfection also released the inhibition of cAMP‐response element‐binding protein (CREB)‐PGC‐1α signalling induced by homocysteine. Additionally, restoration of PGC‐1α expression via AdPGC‐1α infection markedly suppressed VSMCs proliferation through the degradation of NADPH oxidase (NOX1) and reduction of reactive oxygen species (ROS). Collectively, our study identified the role of miR‐217 in regulating VSMCs proliferation and migration, which might serve as a target for atherosclerosis therapy.