Sorafenib, as a first-line drug for advanced hepatocellular carcinoma (HCC), could trigger ferroptosis by inhibiting cystine/glutamate transporter. However, low-level intracellular iron and insufficient activation of AMP-activated protein kinase (AMPK) confer impaired response to sorafenib. In this study, a unique sorafenib nanocomposite, dexterously modified with an iron motif (sora@Fe-MIL), was synthesized to escalate intracellular iron level and activate AMPK, further potentiating the ferroptotic effect of sorafenib. Remarkably, this strategic deployment of sora@Fe-MIL triggered an extensive demise of cancer cells, while manifesting negligible deleterious impact on normal cells. Two prominent ferroptosis biomarkers, Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), underwent pronounced downregulation, underscoring the efficacy of this strategy in inducing ferroptosis. Furthermore, the bioactivity of AMPK was considerably elevated, and its downstream targets were conspicuously inhibited by the treatment with sora@Fe-MIL. Using orthotopic HCC animal models, a substantial suppression of primary in situ tumor growth was observed and RNA sequencing elucidated an elevated degree of ferroptosis and AMPK activation with the treatment of sora@Fe-MIL. In conclusion, we proposed that the meticulously designed strategy for secure and efficacious iron-release and AMPK-activation could significantly potentiate the ferroptotic impact of sorafenib, thus resuscitating its therapeutic response in HCC patients.