Extravasation is a key step in tumor metastasis. Epstein‒Barr virus plays a crucial role in nasopharyngeal carcinoma (NPC) metastasis. However, the functions and molecular mechanisms of Epstein‒Barr virus during tumor cell extravasation remain unclear. Here, we showed that the expression of pyroptosis-associated proteins is greater in the endothelial cells of metastatic NPC tissues than in those of nontumor tissues exosomes derived from NPC cells promoted endothelial cell pyroptosis, vascular permeability, and tumor cell extravasation. Moreover, we found that BART2-5p is abundant in serum exosomes from patients with NPC metastasis and in NPC cells and that it regulates endothelial cell pyroptosis in premetastatic organs via MRE11A. Exosomes containing a BART2-5p inhibitor and AAV-MRE11A attenuated endothelial cell pyroptosis and tumor metastasis. Moreover, in the endothelial cells of metastatic tissues from patients with NPC, the BART2-5p level was positively associated with pyroptosis-related protein expression. Collectively, our findings suggest that exosomal BART2-5p is involved in premetastatic niche formation, identifying secreted BART2-5p as a potential therapeutic target for NPC metastasis. Implications: The finding that secreted BART2-5p is involved in premetastatic niche formation may aid the development of a potential therapeutic target for NPC metastasis.