Neutrophils are the most abundant effector cells of the innate immune system and represent the first line of defense against infection. However, in many common pathologies, including autoimmune diseases, excessive recruitment and activation of neutrophils can drive a chronic inflammatory response leading to unwanted tissue destruction. Several strategies have been investigated to tackle pathologic neutrophil biology and thus provide a novel therapy for chronic inflammatory diseases. The chemokine receptor CXCR2 plays a crucial role in regulating neutrophil homeostasis and is a promising pharmaceutical target. In this study, we evaluated the therapeutic potential of blocking this receptor using anti-CXCR2 mAb in two chronic inflammatory mouse models, atopic dermatitis (AD) and arthritis (RA). After inducing AD, anti-mouse CXCR2 mAb treatment significantly attenuated the clinical severity of the disease, including skin inflammation, dermal and epidermal thickness, and itch-evoked scratching compared to isotype-control treated animals. This mAb treatment also reduces the infiltrations of inflammatory cells to inflamed skin and ear draining lymph nodes. To test our therapeutic regiment in human, we use human CXCR2-knock-in mice. We observed similar results when human CXCR2-knock-in mice were treated with the humanized anti-human CXCR2 mAb. In RA, administration of anti-CXCR2 mAb quickly reversed arthritic clinical symptoms, such as ankle thickness, inflammatory leukocytes infiltration in the synovial space, and loss of cartilage in the ankle joint. This mAb treatment also reduces the infiltration of innate effector cells to the ankle joints and popliteal draining lymph nodes in comparison with isotype control-treated mice. Similar results were observed when human CXCR2-knock-in mice were treated with the humanized anti-human CXCR2 mAb. Our findings suggest that blocking CXCR2 will be a promising therapeutic strategy to treat AD and RA, as well as in other neutrophil-mediated inflammatory conditions where neutrophils are pathogenic, and medical needs are unmet.