The hyper-proliferation and peculiar differentiation of epidermal keratinocytes, as well as lymphocyte infiltration primarily composed of T lymphocytes, are characteristics of psoriasis. Topical therapy is the most often used form of treatment. Plant-derived nutraceutical polyphenols can be delivered using vesicular carriers called phytosomes, which have greater bioavailability and improved drug penetration into the skin than liposomes. A naturally occurring polyphenolic substance, curcumin has been extensively studied for its potential to treat a variety of anti-inflammatory conditions, including psoriasis. The purpose of the current work is to create an optimized Curcumin-Phytosomes gel formulation and employ a mouse-tail model to conduct an in-vivo investigation on albino mice. The in-vivo results validated the formulation's improved permeability and extended release. In psoriatic lesions, the granular layer of the epidermis is significantly diminished. In the mouse tail test, the topical application of phytosomal gel formulation significantly affects drug-antipsoriatic activity (%), orthokeratosis (%), and relative epidermal thickness (%). The standard drug and phytosomal gel have reduced the epidermal thickness to 44.65 ± 1.09% and 43.78 ± 1.21%, respectively. The anti-psoriatic impact of the Curcumin-laden phytosomal gel (1%) was shown to be considerable when compared to the standard medication, with percent drug activity of 56.43±1.25% and 59.65±1.18%, respectively. The scaly areas displayed parakeratosis, whereas the control group displayed orthokeratosis at a rate of 25.76 ± 1.72%. The standard formulation of Tazarotene and the phytosomal gel of Curcumin exhibited orthokeratosis values of 68.59 ± 1.15% and 67.25±1.27%, respectively. These results demonstrated the phytosomal gel-based method's ability to stimulate psoriasis patients' natural epidermal development.