Introduction: Pediatric bronchial asthma (BA) is a heterogeneous inflammatory disorder with rising prevalence in Asia-Pacific regions. Interleukin-22 (IL-22) exhibits paradoxical roles in adult asthma models—promoting inflammation in chronic Aspergillus fumigatus-induced asthma but exerting protective effects in OVA-induced allergic asthma. However, its functional mechanisms in pediatric BA remain unclear. Objectives: To Quantify serum IL-22 levels in acute pediatric BA exacerbations versus remission and healthy controls, elucidate IL-22’s immunomodulatory role in an OVA-induced juvenile mouse model, and identify molecular pathways linking IL-22 to airway inflammation and remodeling. Methods: A prospective case-control study enrolled 104 acute BA patients, 80 remission patients, and 80 healthy children. Serum IL-22 was measured by ELISA, correlated with FeNO, eosinophil count, and total IgE. In parallel, BALB/c mice were randomized into five groups: IL-22- treated, anti-IL-22 antibody-treated, isotype control, OVA-challenged, and saline control. Airway hyperresponsiveness (AHR) was assessed via non-invasive spirometry . Bronchoalveolar lavage fluid (BALF) eosinophils were quantified, and lung tissues underwent H&E/PAS staining and TMT-based proteomics. Immunofluorescence validated MHC-II expression in dendritic cells. Results: Acute BA patients showed significantly elevated serum IL-22 levels compared to remission and healthy controls (P