This study addresses a critical and unresolved issue in hepatocellular carcinoma treatment: the development of lenvatinib resistance. We provide compelling evidence that exosome-derived lnc-FAM72D-3 plays a pivotal role in promoting lenvatinib resistance by remodeling the cytoskeleton of hepatocellular carcinoma cells through the MBNL1/FAK axis. Simultaneously, through validation using both in vivo and in vitro models, we have firmly demonstrated that the combination therapy of FAK inhibitor and lenvatinib can significantly reverse the extent of lenvatinib resistance. Furthermore, the expression levels of lnc-FAM72D-3/MBNL1/FAK in clinically collected specimens from both lenvatinib-resistant and lenvatinib-sensitive patients were consistent with our results.