Psoriasis is a chronic autoimmune skin disorder characterized by keratinocyte hyperproliferation, inflammation, and angiogenesis, significantly impacting patients' quality of life. Current therapeutic strategies, including topical corticosteroids, phototherapy, and systemic biologics, often present limitations such as adverse effects, high costs, and inadequate skin penetration. Transdermal drug delivery offers a promising alternative by enhancing localized drug bioavailability and minimizing systemic side effects. In this study, we investigated the antipsoriatic potential of pemetrexed disodium, a multitargeted antifolate agent, formulated as a transdermal patch in an imiquimod-induced psoriasis mouse model. The patches were prepared using a solvent evaporation technique and optimized for controlled drug release. Mice treated with pemetrexed-loaded transdermal patches exhibited significant dose-dependent reductions in psoriasis severity, as evidenced by improvements in Psoriasis Area and Severity Index (PASI) scores, histopathological analysis, and suppression of inflammatory cytokines (TNF-α, IL-6) assessed via qRT-PCR and ELISA. The highest concentration (0.16 mg/cm) demonstrated the most pronounced therapeutic effects, comparable to the standard ketoconazole treatment. These findings highlight the potential of pemetrexed disodium-loaded transdermal patches as an innovative, targeted therapy for psoriasis, warranting further clinical investigations.