Background: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune dysregulation and elevated levels of interleukin-17 (IL-17), a cytokine implicated in both systemic and local inflammatory responses. Objective: To assess the impact of topical mometasone furoate 0.1% cream on IL-17 levels in both serum and skin tissue of patients with acute and subacute AD, and to compare these levels with healthy controls. Methods: A diagnostic interventional case-control study was conducted on 30 AD patients and 30 age- and sex-matched healthy controls. Clinical severity was evaluated using the SCORAD index and visual analogue scales. IL-17 levels were measured in serum via ELISA and in skin tissue via immunohistochemistry before and after a two-week course of topical mometasone furoate. Results: AD patients exhibited significantly elevated IL-17 levels in both serum and tissue compared to controls. Post-treatment, IL-17 levels decreased markedly in both compartments (serum: 238.12 ± 23.16 to 126.86 ± 10.21 pg/ml, P < 0.001). SCORAD scores also improved significantly (59.7 to 25.7, P < 0.001). ROC analysis revealed serum IL-17 had excellent diagnostic accuracy (AUC = 1.0, sensitivity = 96.7%, specificity = 100%). Conclusion: Elevated level of IL-17 in both tissues & sera of AD patients & its decrease after treatment with one of topical corticosteroids could shed the light on the role of IL-17 on the pathogenesis of AD that needs further investigations. Topical mometasone furoate significantly reduces IL-17 expression both systemically and locally in AD patients, underscoring its dual anti-inflammatory effect and the potential of IL-17 as a biomarker for disease activity and therapeutic response.