SUMMARY : Aims:To investigate the mechanism behind cytotoxic edema formation following subarachnoid hemorrhage (SAH).Methods:We explored the role of aquaporin‐4 (AQP4), inwardly rectifying K⁺4.1 (Kir4.1) channels and their upstream orchestrators p53 and p38MAPK in this process. A p53 inhibitor, pifithrin‐α (PFT‐α) was administered intraperitoneally to rats undergoing SAH by endovascular perforation. Totally, 98 male SD rats were categorized into sham, SAH, SAH+ dimethyl sulfoxide (DMSO), SAH+ 0.2 or 2.0 mg/kg PFT‐α groups. At 24 h after SAH, MRI (diffusion‐weighted imaging [DWI]), immunohistochemistry, and Western blot were used.Results:MRI (DWI) showed a significant cytotoxic edema in the brain following SAH with PFT‐α therapy reducing it. Immunohistochemistry and Western blot showed an increased level of p53, phosphorylated‐p38MAPK and AQP4 and a reduced level of Kir4.1; all of which could be reversed following PFT‐α treatment. Treble labeling staining revealed colocalization of p53 with phosphorylated‐p38MAPK and unmatched expression of AQP4 and Kir4.1 within astrocyte cells.Conclusion:These results indicated p53 mediates the formation of cytotoxic edema in the brain following SAH; an uncoupling expression of AQP4 and Kir4.1 on astrocytic end feets orchestrated by p38MAPK was partly responsible.