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Cancer cells are exposed to major compressive and shearing forces during invasion and metastasis, leading to extensive plasma membrane damage. To survive this mechanical stress, they need to repair membrane injury efficiently. Targeting the membrane repair machinery is thus potentially a new way to prevent invasion and metastasis. We show here that annexin-A2 (ANXA2) is required for membrane repair in MDA-MB-231 cells, a highly invasive triple-negative breast cancer cell line. Mechanistically, we show by fluorescence and electron microscopy that cells fail to reseal membrane damaged by shear stress when ANXA2 is silenced or the protein is inhibited with neutralizing antibody. Silencing of ANXA2 has no effect on proliferation in vitro, and even accelerates migration in wound healing assays, but reduces tumor cell dissemination in both mice and zebrafish. We show that high expression of ANXA2 predicts poor prognosis in high-grade lung, ovarian, gastric and breast cancers. We expect that inhibiting membrane repair will be particularly effective in these aggressive, poor prognosis tumors because they rely on the membrane repair machinery to survive membrane damage during tumor invasion and metastasis. This could be achieved either with monoclonal anti-ANXA2 antibodies, which have been shown to inhibit metastasis of MDA-MB-231 cells, or with small molecule drugs.