Objective To investigate the effects of metformin on the proliferation and inflammatory response of vascular smooth muscle cells (VSMCs) induced by tumor necrosis factor-α (TNF-α) and their possible mechanisms. Methods VSMCs were treated by TNF-α and metformin of different concentrations for 24 h. Concentrations that were most suitable for treatment were selected by the MTT, and VSMCs were divided into the control group, TNF-α group, TNF-α+metformin group, and metformin group. The cell cycle was detected by the flow cytometry. Expressions of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected by the RT-PCR and Western blotting. Expressions of AMPK and p-AMPK were detected by the Western blotting. Results The absorbance value of the group treated by TNF-α of 10 ng/mL significantly increased (P<0.01). The variation of absorbance value of the group treated by metformin of 2 mmol/L was the most significant (P<0.05). The cell rate of G1 phase of the TNF-α+metformin group was significantly lower than that of the control group and higher than that of the TNF-α group. The expressions of iNOS and COX-2 decreased and the expression of p-AMPK increased. Conclusion Metformin can arrest the cell cycle and inhibit the proliferation and inflammatory response of VSMCs induced by TNF-α through activating the AMPK signaling pathway.