Beyond the regulation of cholesterol metabolism, a number of extrahepatic functions of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been increasingly identified. The main purpose of this study was to verify whether PCSK9 expression in vascular smooth muscle cells (VSMC) is influenced by insulin resistance and high glucose (HG). In cultured rat aortic VSMC from lean insulin-sensitive Zucker rats (LZRs) and obese insulin-resistant Zucker rats (OZRs), a classical animal model of insulin resistance, we evaluated PCSK9 expression with or without the monoclonal antibodies against PCSK9 Alirocumab and Evolocumab or the synthetic PCSK9-binding peptide PEP 2-8. Effects and molecular mechanisms underlying altered PCSK9 expression were evaluated by proliferation and migration assay, reactive oxygen species (ROS) production, and involvement of PKC, NADPH-oxidase, MAPK/ERK-1/2 pathway activation. As a result, we found that, in comparison with LZR, VSMC from OZR showed basal PCSK9 overexpression mitigated by Alirocumab, Evolocumab, PEP 2-8, and the inhibitors of PKC, NADPH-oxidase, and MAPK. The finding of PCSK9 upregulation in VSMC from OZR paralleled with increased ROS production, proliferation, and migration. HG increased PCSK9 expression in VSMC from LZR, but not in OZR, via oxidative stress and with effects reduced by PCSK9 inhibitors. These findings suggest that a dysregulation of PCSK9 in VSMC could be involved in vascular damage in metabolic disorders, such as obesity and diabetes.