Updated project metadata. Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a plasma membrane proteoglycan, is highly expressed in intestinal subtype gastric tumours and that this signature associates with patients’ poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer motility and invasion. We also find that SDC4 conjugated with heparan sulfate chains is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis of the molecular implications of SDC4 expression in gastric cancer cells and open new perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumour progression.