Psoriasis is a chronic, inflammatory condition that primarily affects the skin, hair, and joints and is associated with significant humanistic and economic consequences. This work induced psoriasis in mice using an imiquimod 5% cream, an immune response modifier that can cause psoriasis-like skin inflammation when given orally. Paquinimod is prepared as an ointment and has been topically given to mice before imiquimod application. In this study, albino mice were allocated into five groups and treated as follows: the control group received only a daily application of cream based on shaved back (62.5mg/2cm) with a daily topical dose of ointment for 14 consecutive days with the oral vehicle. The Imiquimod group received a daily topical dose of vehicle one hour before imiquimod 5% application on shaved back (62.5mg/2cm) for 14 consecutive days. The paquinimod-treated group received daily topical doses of paquinimod one hour before imiquimod 5% application on shaved back (62.5mg/2cm) for 14 consecutive days. Clobetasol -treated group received a daily topical dose of clobetasol ointment (62.5mg/2cm) one hour before imiquimod 5% application on shaved back (62.5mg/2cm) for 14 consecutive days. Paquinimod, the only group that received a daily oral dose of paquinimod for 14 consecutive days. The current study found that the administration of paquinimod ointment resulted in a significant decline in TNF-α, IL-23, IL17 level, reduced psoriasis area and severity index, spleen index, skin thickness, and gene expression of TNF-α, Nf-KB, IL-1B, IL-17in the (Paquinimod ointment+imiquimod) group substantially more than that in the (vehicle ointment+imiquimod) groups. In conclusion, paquinimod has a powerful ameliorating effect that can reduce the IMQ-induced psoriasis-like inflammation in a mouse model. As a result, we have every reason to believe that paquinimod will be utilized to treat psoriasis. Keywords: Psoriasis; Paquinimod; Imiquimod; IL-23; IL-17; TNF-α.