While the involvement of actin polymerization in membrane protrusion is well-established, we have a more limited understanding of the role of transmembrane water flow in cell motility. Here we investigate the role of water influx in neutrophil migration. These cells undergo directed movement to sites of injury and infection. Chemoattractant exposure increases cell volume and potentiates neutrophil migration, but the causal link between these processes is not known. Using a genome-wide CRISPR screen, we identify the regulators of the chemoattractant-induced neutrophil swelling, including NHE1, AE2, PI3K-gamma, and CA2. Through NHE1 inhibition in primary human neutrophils, we show that cell swelling is both necessary and sufficient for rapid migration following chemoattractant stimulation. Our data demonstrate that cell swelling complements cytoskeletal inputs for chemoattractant-induced potentiation of migration.