The mesenchymal sub-type of triple negative breast cancer (MES-TNBC) has a highly aggressive behavior and worse prognosis, due to its invasive and stem-like features, that correlate with metastatic dissemination and resistance to therapies. Furthermore, MES-TNBC is characterized by the expression of molecular markers related to the epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs). The altered expression of alphavbeta(3) integrin has been well established as a driver of cancer progression, stemness, and metastasis. Here, we showed that the high levels of alphavbeta(3) are associated with MES-TNBC and therefore exploited the possibility to target this integrin to reduce the aggressiveness of this carcinoma. To this aim, MES-TNBC cells were treated with a novel peptide, named psiRGDechi, that we recently developed and characterized for its ability to selectively bind and inhibit alphavbeta(3) integrin. Notably, psiRGDechi was able to hamper adhesion, migration, and invasion of MES-TNBC cells, as well as the capability of these cells to form vascular-like structures and mammospheres. In addition, this peptide reversed EMT program inhibits mesenchymal markers. These findings show that targeting alphavbeta(3) integrin by psiRGDechi, it is possible to inhibit some of the malignant properties of MES-TNBC phenotype.