Psoriasis involves considerable dermal inflammation, resulting from an imbalance in which pre-oxidants surpass the skin's antioxidant capability. This persistent autoimmune skin condition, characterized by T-cell activity, features excessive epidermal thickening, impaired cell differentiation, and heightened vascularization in the dermis. Contemporary therapy approaches aim to enhance cost-effectiveness, longevity of use, and safety. The present study is a novel method employing polymer-lipid hybrid nanoparticles for the targeted delivery of myrtenol (MYR), a recognized anti-inflammatory and antioxidant biomolecule, directly to the skin. Hydrogel, with Carbopol 971 P serving as the gelling agent for topical application, were developed to treat psoriasis by infusing them with MYR and polymer-lipid NPs (MYR-NPs gel). Enhanced drug loading, optimal release dynamics, extended stability, and efficient reactive oxygen species (ROS) scavenging were only a few of the several advantageous traits the MYR-NPs gel shown. In human keratinocyte cells, in vitro studies found that MYR-NPs gel greatly slowed keratinocyte proliferation, induced death, and lowered IL-6-mediated inflammatory signaling. Effective dermal penetration of MYR-NPs gel on imiquimod (IMQ) -induced psoriatic lesions in a mouse model produced a marked reduction in epidermal thickness and the restoration of normal epidermal development. These results highlight the potential of MYR-NPs gel as a suitable nanomedicine for psoriasis treatment including higher ROS scavenging, enhanced cellular absorption, improved skin penetration and drug retention, and less hyperactive immune cell activity. © © 2025. Published by Elsevier B.V.