This study aimed to evaluate whether the knockout of transient receptor potential melastatin 4 (TRPM4) could reduce cerebral edema and improve neurologic outcome in a mouse model of status epilepticus (SE). Wild-type (WT) (n = 61) and Trpm4^–/– mice (n = 61) with behavioral seizures induced by lithium (10 mEq/kg) and pilocarpine (30–40 mg/kg) were terminated 2.5 hours after the onset of SE. After SE, 28 WT-SE and 27 Trpm4^–/–-SE mice were observed for 28 days and assessed for survival and cognitive function; the others were killed after 24 hours, 72 hours, or 7 days, and evaluated for cerebral edema and histological injury. In comparison to WT-SE mice, the mortality and cognitive deficit for Trpm4^–/–-SE mice following SE after 28 days were significantly ameliorated. Trpm4^–/–-SE mice also showed less water content and cerebral edema assessed by magnetic resonance imaging, and decreased blood-brain barrier breakdown after SE. Moreover, Trpm4 deficiency significantly mitigated neuronal loss, cellular necrosis and apoptosis in the hippocampus and piriform cortex and mitigated astrocytosis and microgliosis. In conclusion, this study suggests that Trmp4 may represent a new target for improving outcomes after SE.