Ischemic stroke often causes devastating damage to human life and health. Excess production of reactive oxygen species (ROS) during thrombolysis will paradoxically result in neuronal injury. Neuroprotection from reperfusion injury must overcome the challenge of crossing the blood-brain barrier (BBB). A strategy including thrombolysis and ROS scavenging accompanied by BBB penetration is highly desirable for improving combination therapies in ischemic stroke. Herein, urokinase plasminogen activator (uPA) loaded on black phosphorus nanosheets (BPNs) is tested as a nanodrug for sequential thrombolysis and neuroprotection. The in vitro thrombolysis shows that the uPA-loaded BPNs can efficiently deliver uPA for thrombus dissolution. The residual BPNs after uPA release exhibit ROS scavenging effects, especially for the most common H2O2 and ˙OH species. Moreover, in vivo studies show that the BPNs can cross the BBB with the assistance of laser irradiation, owing to their good photothermal properties. Further experiments show the effectiveness of BPNs for attenuating reperfusion injury and achieving neuroprotection. These results highlight the promising potential of the present BPN-based nanodrugs for the treatment of ROS-related diseases.