Mevastatin (HMG-CoA reductase inhibitor) isolated from Penicillium citrinum is known to the first statin that inhibitor of cholesterol synthesis. Recently, several clinical reports of other statins suggest its role on reducing the severity of psoriasis, but the available evidence on cellular/molecular level of mevastatin is unclear. Thus, this study was to determine the molecular/cellular mechanism of mevastatin using TNF-α/IL-17A stimulated HaCaT cells. First, the safety and effectiveness of mevastatin were confirmed through the comparative experiment of five statin derivatives. Mevastatin decreased mRNA levels of cytokines (IL-1α/β, IL-6, and IL-8), chemokine (CC motif) ligand 20 (CCL20), and keratin proteins (Keratin 5/14/6/16) known to be overexpressed in psoriasis. In addition, mevastatin significantly reduced phosphorylation of NF-κB, MAPKs and STAT3 in TNF-α/IL-17 signaling pathway. Moreover, mevastatin specifically suppressed keratin 5/14 proteins expressed in the keratinocyte differentiation process of the basal layer and keratin 6A/16 overexpressed in patients with psoriasis. These results imply that mevastatin not only can inhibit psoriasis-induced inflammatory cytokines and chemokines, but also can suppress psoriasis-related keratin proteins.