Psoriasis is an immune-mediated skin disorder, which encounters therapeutic challenges on topical drug development due to the unclear mechanism, complicated morphological and physiological changes in the skin. In this study, imiquimod (IMQ)-induced psoriatic mouse skin was chosen as the in vitro pathological model to explore the penetration behaviors of drugs and nanoparticles (NPs). Compared to those in normal skin, significantly higher penetration and skin accumulation were observed in psoriatic skin for all of the three model drugs. Furthermore, by taking three sized FluoSpheres® as model NPs, confocal laser scanning microscopy demonstrated that the penetration pathways of NPs no longer followed the hair follicles channels, instead they were more widely distributed in the psoriatic skin. To ameliorate the conditions of poor aqueous solubility and chemical stability, overcome skin barriers, and enhance in vivo anti-psoriatic activity, curcumin (Cur) loaded poly (lactic-co-glycolic acid) (PLGA) NPs were fabricated and administered by topical route to treat IMQ-induced psoriasis-like mouse model. Spherical Cur-NPs with the mean particle sizes of 50 nm and 150 nm both exhibited significantly stronger anti-proliferation effect than Cur suspension on HaCaT cells, as well as higher penetration and accumulation in normal and psoriatic skin in vitro. Interestingly, the NPs’ size effect, in terms of their penetration and accumulation behaviors, was more pronounced for psoriatic skin. To compare the nanosizing effect of these Cur-NPs, the IMQ-induced psoriasis-like mice were treated with blank gel, Cur gel, 50 nm sized NPs gel, 150 nm sized NPs gel or tracrolimus cream (positive control), respectively. The results indicated that Cur-NPs hydrogel has a superior v performance to Cur hydrogel on pathological model in terms of morphological evaluation, biomarkers at mRNA, and protein levels. In conclusion, the alternation of the psoriatic skin structure and related drug and NPs penetration should be considered in topical drug formulation and further clinical practice for psoriasis therapy. Encapsulation of Cur into PLGA NPs could facilitate lipophilic Cur’s dispersion, sustained-release, accumulation, and penetration across the skin and into the blood circulation, which significantly improves anti-psoriasis activity in mice, showing greater potential of topical treatment for psoriasis.