The biological active cargo of leukemia-derived extracellular vesicles (EVs) favours a wide variety of cancer-supportive mechanisms, including aberrant proliferative signalling, immune escape and drug resistance. However, whether and in which extent anti-neoplastic drugs affect EV cargo sorting is often underestimated. Vorinostat, also known as SAHA, has shown promising results against leukemia , and reached important clinical goals when combined with other therapeutics. Nevertheless, SAHA-mediated effects on intercellular communication via EVs remains unknown. Here, we found SAHA to significantly affects the overall cargo associated with leukemia-derived EVs. Interestingly, SAHA differently affects the intracellular and vesicular levels of miR194-5p and BCLAF1 ratio, which imbalance was previously shown to regulate cell survival and differentiation in leukemic cells. Moreover, in silico evaluations predicted SAHA to skew the tumoral potential ascribed to leukemic EVs, hypothesis confirmed by functional evaluations. Finally, EVs from SAHA-treated leukemic cells may condition the sensitivity of surrounding cancer cells to other antineoplastic agents. Altogether we showed that SAHA leads leukemic cells towards apoptosis while reverting the oncologic significance ascribed to leukemia-derived EVs, eventually affecting the efficacy, and therefore selection, of other therapeutics to use for combinatorial purposes.