To the best of our knowledge, this study is the first to show that S100A11 directly participates in and even inhibits the process of ANXA1 translocation to the nucleus and the first step to verify that S100A11 protects against ischemic stroke by regulating ANXA1 subcellular localization and provides a broader view of S100A11 function after MCAO. Here, ANXA1 is linked to ischemic stroke.