IL-5/IL-5R signaling is crucial for eosinophil function and has therapeutic implications for inflammatory diseases like asthma. We developed a humanized B-hIL5/hIL5RA mouse model to assess IL-5/IL5R-targeting therapies. Successful generation of the model was confirmed, and stimulation with human IL5 increased eosinophil proportions in the blood, validating functionality. In an asthma-like disease model, treatment with mepolizumab or benralizumab analog significantly reduced eosinophil numbers in bronchioalveolar fluid and lung tissue, highlighting the model’s utility for testing human IL-5/IL-5RA modulators.