Triple-negative breast cancer (TNBC) is a unique breast cancer subtype with high risk for metastasis and recurrence and poor prognosis. Epithelial-mesenchymal transition (EMT) endows epithelial cells with mobility to move to distant sites, which is essential for metastasis of TNBC to organs including lung. Autophagy, an intracellular degradation process through forming double-layered lipid autophagosome that transports cytosolic cargoes into lysosome after autophagosome-lysosome fusion, is involved in EMT of cancer cells. Here, we report a role for FRAX486, a potent P21- activated kinase 2 (PAK2) inhibitor, in TNBC suppression both in vitro and in vivo by blocking autophagy. Mechanistically, FRAX486 inhibits autophagy in TNBC cells through targeting PAK2, leading to the ubiquitination and proteasomal degradation of STX17 that mediates autophagosome-lysosome fusion. The inhibition of autophagy by FRAX486 causes up-regulation of epithelial marker protein E-cadherin and thus suppresses the migration and metastasis of TNBC cells. The effects of FRAX486 in TNBC metastasis suppression are verified to be relied on PAK2 and autophagy inhibition. Together, our results provide a molecular basis for the application of FRAX486 as a potential option to inhibit the metastasis of TNBC.