We have recently shown that mast cells (MCs), which constitute an important part of the tumor microenvironment (TME), can be directly activated by cancer cells under conditions that recapitulate cell to cell contact. However, MCs are often detected in the tumor periphery rather than intratumorally. Therefore, we investigated the possibility of MC activation by cancer cell–derived extracellular vesicles (EVs). Here we show that exposure of MCs to EVs derived from pancreatic cancer cells or non–small cell lung carcinoma results in MC activation, evident by the increased phosphorylation of the ERK1/2 MAP kinases. Further, we show that, similarly to activation by cancer cell contact, activation by EVs is dependent on the ecto enzyme CD73 that mediates extracellular formation of adenosine and on signaling by the A3 adenosine receptor. Finally, we show that activation by either cell contact or EVs upregulates expression of angiogenic and tissue remodeling genes, including IL8, IL6, VEGF, and amphiregulin. Collectively, our findings indicate that both intratumorally localized MCs and peripheral MCs are activated and reprogrammed in the TME either by contact with the cancer cells or by their released EVs.