The proliferation of vascular smooth muscle cells plays a crucial role in pathogenesis of cardiovascular disease. The principal objective of this study was to determine the effects of Ojeoksan (OJS) on human aortic smooth muscle cell (HASMC) proliferation induced by tumor necrosis factor α (TNF-aα). Thymidine incorporation after TNF-α treatment was increased and this effect was inhibited significantly by OJS treatment. HASMC proliferation and migration by kinetic live cell imaging were also reduced by treatment with OJS. TNF-α induced the expression of cyclins/cyclin-dependent kinases (CDKs) and reduced the expression of p21waf1/cip1/p27kip1. However, OJS also attenuated the expression of TNF-α-induced cell-cycle regulatory proteins. The results of Western blot analysis demonstrated that the TNF-α treated HASMC secreted gelatinases, probably including MMP-2/-9, which may be involved in the invasion and migration of HASMC. Additionally, OJS suppressed the mRNA expression levels of matrix metalloproteinase-2/-9 (MMP-2/-9) in a dose-dependent manner. OJS inhibited the production of TNF-α-induced hydrogen peroxide (H2O2) and the formation of DCF-sensitive intracellular reactive oxygen species (ROS). Further, OJS suppressed the nuclear translocation and phosphorylation of inhibitor of kappa B-α (IκB-α) of nuclear factor κB (NF-κB) under TNF-α conditions. Our results demonstrate that OJS exerts inhibitory effects on TNF-α-induced HASMC proliferation and migration, suggesting the involvement of the inhibition of both MMP-2 and MMP-9 expressions, and the downregulation of ROS/NF-κB signaling. Thus, herbal decoction OJS may be a possible therapeutic approach to the inhibition of cardiovascular disease including atherosclerosis.