Tissue plasminogen activator (tPA) is the only FDA approved thrombolytic drug for acute ischemic stroke but concerns regarding its limitations remain. Here, we developed a new strategy by incorporating tPA into porous magnetic iron oxide (Fe3O4)-microrods (tPA-MRs) for targeted thrombolytic therapy in ischemic stroke induced by distal middle cerebral artery occlusion. We showed that intra-arterial injection of tPA-MRs could target the cerebral blood clot in vivo under the guidance of an external magnet, where tPA was subsequently released at the site of embolism. When applied with an external rotating magnetic field, rotating tPA-MRs significantly improved not only the mass transport of the tPA-clot reaction, but also mechanically disrupted the clot network, which thus increased clot interaction and penetration of tPA. Importantly, intravenously injected MRs could be discharged from the kidney, and the function of liver and kidney were not damaged at different durations after administration of tPA-MRs. Our data suggest that tPA-MRs overcome the limitations of thrombolytic therapy with tPA alone, which may be not only just for the treatment of ischemic stroke but also have majorly impact on other thrombotic diseases.