<p>Psoriasis is a persistent inflammatory dermatological disorder characterized by dysregulated hyperproliferation of keratinocytes and pathological immune cell infiltration, impacting a significant population globally. Conventional systemic therapies, including oral and injectable formulations, are often limited by adverse off-target effects, which limit their utility in long-term clinical management. To address this challenge, we developed a soluble bilayered microneedle patch (Methotrexate and dexamethasone co-loaded bilayer microneedles, MTX@DXM-MNs), which consists of an outer layer of gelatine-polyvinyl alcohol hydrogel loaded with dexamethasone (DXM) and an inner layer of aminocrystallized hyaluronic acid methacrylate hydrogel loaded with methotrexate (MTX). The patch successfully traversed imiquimod (IMQ)-induced thickened epidermis in murine models to achieve intralesional drug delivery and effectively alleviate psoriasis-like skin inflammation. Versus tacrolimus ointment (positive control), MTX@DXM-MNs markedly alleviated the manifestations of stratum corneum thickening, erythema, and scaling in a mouse model and attenuated the levels of inflammatory mediators in skin tissues and peripheral blood as well as splenic indices. In conclusion, the MTX@DXM-MN bilayered microneedle patch provides a new strategy for the efficient and safe treatment of psoriasis through the temporal and spatial synergistic effects of an outer layer for the immediate release of a hormone and an inner layer for the slow release of an immunosuppressant. Thus, this patch has potential as a future clinical alternative for the treatment of psoriasis.</p>