Asthma remains an important cause of morbidity and mortality. We herein provide for the first time a preclinical proof-of-concept for a novel therapeutic approach for allergic asthma using an anti-IL-7Rα mAb, which blocks both IL-7R and TSLPR. We used a murine asthma model in which mice received 4 weekly percutaneous sensitizations followed by 2 weekly intranasal (IN) challenges with total house dust mite (HDM) extracts as allergen. This model corresponds to a mixed asthma phenotype in which the bronchoalveolar inflammation comprises both neutrophils and eosinophils. Asthmatic mice were then treated with an anti-IL-7Rα mAb or an isotype control every other day during the 2 weeks of IN challenges. Anti-IL-7Rα mAb blocks STAT5 phosphorylation in mouse CD4+ T cells induced by either IL-7 or TSLP. Compared to control animals, anti-IL-7Rα-treated mice showed significantly lower airway resistance in response to methacholine as measured by flexiVent, associated with an improvement in lung histology. Anti-IL-7Rα treatment significantly decreased the mRNA expression of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL5/RANTES) in lung tissue, decreased the secretion of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CXCL1 and CCL11/eotaxin) in bronchoalveolar lavage fluid as measured by luminex, and decreased serum HDM-specific IgE as measured by ELISA. Leukocyte phenotyping by flow cytometry revealed a reduction of eosinophils, total lymphocytes, T cells, and especially ILC2 in lung and in BALF in anti-IL-7Rα-treated mice. Targeting the IL-7Rα by a mAb, through its broad mechanisms of action, presents as a potential therapeutic approach for asthma.