The α9β1 integrin accelerates cell migration through binding of spermidine/spermine acetyltransferase (SSAT) to the α9 cytoplasmic domain. We now show that SSAT enhances α9-mediated migration specifically through catabolism of spermidine and/or spermine. Because spermine and spermidine are effective blockers of K⁺ ion efflux through inward-rectifier K⁺ (Kir) channels, we examined the involvement of Kir channels in this pathway. The Kir channel inhibitor, barium, or knockdown of a single subunit, Kir4.2, specifically inhibited α9-dependent cell migration. α9β1 and Kir4.2 colocalized in focal adhesions at the leading edge of migrating cells and inhibition or knockdown of Kir4.2 caused reduced persistence and an increased number of lamellipodial extensions in cells migrating on an α9β1 ligand. These results identify a pathway through which the α9 integrin subunit stimulates cell migration by localized polyamine catabolism and modulation of Kir channel function.