AbstractDiosmin is a flavonoid with promising anti-inflammatory and antioxidant properties. However, it has difficult physicochemical characteristics since its solubility demands a pH level of 12, which has an impact on the drug’s bioavailability. The aim of this work is the development and characterization of diosmin nanocrystals using anti-solvent precipitation technique to be used for topical treatment of psoriasis. Results revealed that diosmin nanocrystals stabilized with hydroxypropyl methylcellulose (HPMC E15) in ratio (diosmin:polymer; 1:1) reached the desired particle size (276.9 ± 16.49 nm); provided promising colloidal properties and possessed high drug release profile. Additionally, in-vivo assessment was carried out to evaluate and compare the activities of diosmin nanocrystal gel using three different doses and diosmin powder gel in alleviating imiquimod-induced psoriasis in rats and investigating their possible anti-inflammatory mechanisms. Herein, 125 mg of 5% imiquimod cream (IMQ) was applied topically for 5 consecutive days on the shaved backs of rats to induce psoriasis. Diosmin nanocrystal gel especially in the highest dose used offered the best anti-inflammatory effect. This was confirmed by causing the most statistically significant reduction in the psoriasis area severity index (PASI) score and the serum inflammatory cytokines levels. Furthermore, it was capable of maintaining the balance between T helper (Th17) and T regulatory (Treg) cells. Moreover, it tackled TLR7/8/NF-κB, miRNA-31, AKT/mTOR/P70S6K and elevated the TNFAIP3/A20 (a negative regulator of NF-κB) expression in psoriatic skin tissues. This highlights the role of diosmin nanocrystal gel in tackling imiquimod-induced psoriasis in rats, and thus it could be a novel promising therapy for psoriasis.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1007/s10787-023-01198-w.