Background: Psoriasis, autoimmune chronic inflammatory skin disease, affects 2-3% of population. It causes poor life-quality due to its disfiguring lesions and co-morbidities. Interleukin (IL)-23/T-helper (Th)-17 &IL-23/Th-22 axes activation, signal transducer and activator of transcription (STAT)-3 pathway stimulation and proinflammatory cytokines (IL-6, IL-17, IL-22 &TNF-α) overproduction are psoriasis main mechanisms. Psoriasis conventional treatment has many adverse effects as immunosuppression and hepatotoxicity with consequent lack of patients' compliance. Aim of work: Evaluating the probable curative effect of blocking STAT-3 pathway using ochromycinone [an STA-21 (STAT-3 inhibitor)] on Imiquimod (IMQ)-induced psoriasis model in adult male albino rats.  Materials &Methods: 1 cm² back skin was shaved in twenty-four adult male albino rats. They grouped into; control group [group-I], IMQ group [group-II, received 20mg/cm² IMQ-5% topically on the shaved skin for 17 days] & IMQ/STA-21 group [group-III, given daily 3.5mg/kg ochromycinone intraperitoneal injection for 2 weeks]. Psoriasis Area &Severity Index (PASI)-scoring and biochemical, histological, immunohistochemical [for IL-23, STAT-3, Ki-67, connexin (Cx)-26 &vascular endothelial growth factor (VEGF)] and statistical studies were done. Results: IMQ produced psoriasis-like skin lesions (inflammation, epidermal proliferation & angiogenesis). However, the use of STA-21 marvelously ameliorated these lesions. Conclusion:  Topical IMQ provoked psoriasis-like lesions concerning gross, biochemical &histological features. These resulted from IL-23/Th-17 &IL-23/Th-22 axes activation, proinflammatory cytokines production that acted via STAT-3 pathway activation. The use of an STA-21 (STAT-3 inhibitor) as ochromycinone showed amazing improvement of these lesions. Thus, blocking STAT-3 might be a promising treatment for psoriasis instead of the traditional therapy with its marked side-effects.