AbstractBone is the second leading metastatic site for hepatocellular carcinoma (HCC). Patients with HCC and bone metastasis suffer poor quality of life and reduced survival time. Extracellular vesicles (EVs) are widely involved in HCC formation and metastasis. However, the communication between primary HCC and bone lesions mediated by EVs remains unclear and the possible effect of bone metastasis on the progression of HCC remains largely unknown. Here, bone‐metastasized HCC‐derived EVs (BM‐EVs) are found to localize to orthotropic HCC cells and promote HCC progression. Mechanistically, miR‐3190‐5p (miR‐3190) is upregulated in intracellular HCC cells isolated from bone lesions as well as in their derived EVs. miR‐3190 in BM‐EVs is transferred into orthotopic tumor cells and enhances their metastatic capacity by downregulating AlkB homolog 5 (ALKBH5) expression. Decreased level ofALKBH5exacerbates the prometastatic characteristics of HCC by modulating gene expression in N6‐methyladenosine‐dependent and ‐independent ways. Finally, antagomir‐miR‐3190‐loaded liposomes with HCC affinity successfully suppress HCC progression in mice treated with BM‐EVs. These findings reveal that BM‐EVs initiate prometastatic cascades in orthotopic HCC by transferring ALKBH5‐targeting miR‐3190 and miR‐3190 is serving as a promising therapeutic target for inhibiting the progression of HCC in patients with bone metastasis.