Cerebral ischemia-reperfusion injury is one of the most severe diseases in terms of mortality and disability, which seriously threatens human life and health. In clinical treatment, drug thrombolysis or mechanical interventional thrombolysis are used to quickly restore the blood supply of ischemic brain tissue. But with the rapid recovery of blood flow, complex pathophysiological processes such as oxidative stress and inflammation will further aggravate brain tissue damage, namely cerebral ischemia-reperfusion injury, for which there is no effective treatment. Recent studies have shown that the medical community has paid the role of inflammation and pyroptosis in cerebral ischemia-reperfusion injury more and more attention. And Caspase-1 was found to play a vital role in regulating inflammation pathways and pyroptosis in many inflammation-associated diseases, especially in cerebral ischemia-reperfusion injury. Not only that, Caspase-1 inhibitors have been shown to reduce the damage of cerebral ischemia-reperfusion injury by inhibiting inflammation and pyroptosis. And the Caspase-1 inhibitor, Belnacasan, has been proved to modify the active site of Caspase-1 and lead to the blocking of Caspase-1, thus correlating with tissue protection of inflammatory diseases in animal models. Therefore, it’s essential to screen and design potential Caspase-1 inhibitors to reduce cerebral ischemia-reperfusion injury and protect brain function by reducing inflammation and pyroptosis, which provides a new idea for clinical treatment of the cerebral ischemia-reperfusion injury. This study applied a group of computer-aided technology, such as Discovery Studio 4.5, Schrodinger, and PyMol, to screen and assess potential Caspase-1 inhibitors. Moreover, the ADME (absorption, distribution, metabolism, excretion) and TOPKAT (Toxicity Prediction by Computer Assisted Technology) molecules of Discovery Studio 4.5 were conducted to evaluate molecules' pharmacological and toxicological features. Then, precise molecular docking was applied to assess the binding mechanism and affinity between Caspase-1 and selected compounds. Besides, molecular dynamics simulations were performed to determine the stability of ligand-receptor complexes in the natural environment. In summary, this study lists promising drug candidates and their pharmacological properties, promoting the development of Caspase-1 inhibitors and deepening the understanding of the interaction between inhibitors and Caspase-1.