Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as Interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I type II interferons (IFN). Since each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, we hypothesized that lung-restricted Jak1 inhibition may confer therapeutic benefit. To test this idea, we synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed Signal Transducer and Activator of Transcription 6 (STAT6) activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin (OVA)-induced lung inflammation in both murine and guinea pig asthma models, and improved allergen induced airway hyper-responsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophilic inflammation than a systemic corticosteroid. The inhibitor iJak-381 strongly reduced lung pathology, without affecting systemic Jak1 activity. Our data show that local inhibition of Jak1 in the lung can suppress lung inflammation without conferring systemic Jak inhibition in mice, suggesting that this strategy might be effective for treating asthma.