A growing body of evidence suggests that the immune checkpoint inhibitory receptor VISTA plays a central role in the regulation of innate immunity in the settings of inflammatory diseases and cancer. Neutrophils are among the cells that have the highest membrane density of surface VISTA. In this study, targeting VISTA on neutrophils with a monoclonal antibody resulted in a striking reduction in their lipopolysaccharide (LPS)- and chemokine-induced peripheral accumulation but did not reduce neutrophil levels at steady state. Fc receptor engagement and macrophages were required for the effects of anti-VISTA antibody on neutrophils. Concomitant with reduced peripheral neutrophil numbers, targeting VISTA increased neutrophil clearance by macrophages in the liver. In a murine model of neutrophil-mediated arthritis, anti-VISTA antibody treatment ameliorated disease severity, which was associated with reduced myeloperoxidase activity in the joints. These studies identify a novel therapeutic opportunity for targeting VISTA to control neutrophil-mediated inflammation and tissue injury.