Nanophytosomes represent an effective choice for topical drug delivery systems thanks to their small size, general non-toxicity, ease of functionalization and high surface to volume ratio. The goal of the current study was to investigate the potential benefits of using Hypericum perforatum extract nanogel as a means of improving skin penetration and prolonging skin deposition in dermatitis similar to psoriasis. Nanophytosomes (NPs) were developed, optimised and thoroughly characterised. The optimised NPs were then placed in a Carbopol gel base matrix and tested ex-vivo (skin penetration and dermatokinetic) and in-vivo (antipsoriatic activity in an Imiquimod-induced psoriatic rat model). The optimised NPs had a spherical form and entrapment efficiency of 69.68% with a nanosized and zeta potential of 168 nm and -10.37mV, respectively. XRD spectra and transmission electron microscopy tests confirmed the plant botanical encapsulation in the NPs. Following 60 days of storage at 40 ± 2°C/75 ± 5% RH, the optimised formula remained relatively stable. As compared to extract gel, nano-gel showed a much-improved ex vivo permeability profile and considerable drug deposition in the viable epidermal-dermal layers. When developed nano-gel was applied topically to a rat model of psoriasis, it demonstrated distinct in vivo anti-psoriatic efficacy in terms of drug activity and reduction of epidermal thickness in comparison to other formulations and the control. ELISA and histopathologic studies also demonstrated that nano-organogel had improved skin integrity and downregulated inflammatory markers (IL-17, IL-6, IFN-γ and MCP-1). Findings suggest that a developed plant botanicals-based nanogel has a potential for the treatment of psoriasis-like dermatitis with better skin retention and effectiveness.