The ETS transcription factor Fli-1, known for regulating the vitality of pericyte in mice, has not been thoroughly investigated in traumatic brain injury (TBI). In this study, we used a mouse TBI model to demonstrate that Fli-1 expression in pericyte within the ipsilateral hippocampus is significantly increased following TBI and is associated with pericyte loss. Interfering with Fli-1 expression in pericyte disrupted their interactions with microglia, which in turn inhibited the transformation of microglia to a pro-inflammatory phenotype. Administration of Fli-1 siRNA via lateral ventricle injection reduced pericyte loss, microglial activation, and neuroinflammation induced by TBI. Additionally, Fli-1 siRNA treatment reduced neurological damage in the hippocampus and improved memory and cognitive function. Overall, our findings suggest that Fli-1 expression in pericyte is closely linked to pericyte apoptosis and pericyte-microglia interactions. Inhibiting Fli-1 could mitigate pericyte loss, neuroinflammation, blood-brain barrier disruption, and cognitive decline, indicating that targeting Fli-1 may be a viable clinical strategy for TBI intervention.