Psoriasis is a persistent cutaneous disorder involving an imbalance in immune regulation, oxidative stress, and abnormal epidermal proliferation. This study evaluated the therapeutic efficacy of Ecballium elaterium (EE) balm compared with clobetasol propionate (0.05%) (CLO) in rats with psoriasis-like lesions induced by topical imiquimod (IMQ). A total of twenty-four adult male of the Wistar strain were randomly allocated to four groups comprising: control (healthy rats), IMQ-induced psoriasis, IMQ + EE balm, and IMQ + clobetasol. Psoriasis was induced by topical application of 5% imiquimod. Treatments were administered daily. Disease severity, histological changes, oxidative stress markers, serum tumor necrosis factor-α (TNF-α), and biochemical parameters were evaluated. EE balm markedly improved psoriatic lesions and reduced psoriasis severity scores in imiquimod-treated rats. Biochemical analyses indicated that EE balm produced fewer disturbances in hepatic and lipid parameters than clobetasol, notably by preventing alanine aminotransferase elevation (EE: 62.20 ± 3.09; CLO: 89 ± 6.08) and lowering total cholesterol (EE: 0.47 ± 0.08; CLO: 0.63 ± 0.03). However, serum triglyceride (EE: 0.61 ± 0.03) and creatinine concentrations (EE: 6.03 ± 0.23) remained elevated. Serum TNF-α levels, markedly elevated in imiquimod-treated rats, were significantly reduced following EE balm and clobetasol treatments compared with the IMQ experimental set (p < 0.001). EE balm also mitigated oxidative stress by lowering thiobarbituric acid reactive substances (TBARS) levels in serum and erythrocytes in the IMQ group. It also restored antioxidant activities, including catalase (IMQ: 3.06 ± 0.79; EE: 4.24 ± 0.73), super oxide dismutase (IMQ: 03.17 ± 1.01; EE: 18.24 ± 1.90), glutathione peroxidase (EE: 31.25 ± 4.99). Additionally, glutathione s-transferase activity was improved in serum and erythrocytes (EE: 09.96 ± 2.29), as were reduced glutathione levels (IMQ: 0.0021 ± 0.0007; EE: 0.0042 ± 0.001). In an imiquimod-induced psoriasis rat model, Ecballium elaterium balm reduced disease severity, oxidative stress, and inflammatory markers, with systemic biochemical changes. Despite these promising findings, this research is still in its early stages based on a single preclinical model.