Updated project metadata. Hypoxia, a condition of low oxygenation frequently found in triple-negative breast tumors, is often related to increased extracellular vesicle (EV) secretion and favors cell invasion, which is a crucial step for metastasis. Cell invasion is a complex process in which cell morphology is altered due to F-actin cytoskeleton polarization and the establishment of dynamic focal adhesion spots, which coupled with ECM remodeling enables cells to migrate through tissues seeking a new developmental niche. In our in-depth investigation over the invasive properties triggered by TNBC-derived hypoxic small EVs (SEVh) in vitro, we analyzed the morphological, phenotypical and proteomic distinctions promoted by hypoxia and/or SEVh signaling in TNBC cells. SEVh was fully characterized and showed a distinct proteome and abundance profile from its normoxic counterparts. SEVh promotes invasive behaviors exclusively in normoxia, including pro-migratory morphology, invadopodia development, ECM degradation and gelatinase secretion, which indicates the importance of SEVh response on hypoxic settings in tumor progression. In hypoxia, SEVh was responsible for proteolytic and catabolic pathway inducement, interfering with integrin availability and gelatinase expression. Protein profiling of SEVh-treated, normoxic cells indicate a baseline favoring of metabolic processes and cell cycle, modulating cell health away from apoptotic pathways that are enriched in hypoxia. Overall, our results demonstrate the importance of hypoxic signaling via SEV in a tumoral setting for the early establishment of metastasis.