Long‐term neurological deficits after severe traumatic brain injury (TBI), including cognitive dysfunction and emotional impairments, can significantly impair rehabilitation. Glial activation induced by inflammatory response is involved in the neurological deficits post‐TBI. This study aimed to investigate the role of the stimulator of interferon genes (STING)–nucleotide‐binding oligomerization domain‐like receptor pyrin domain‐containing‐3 (NLRP3) signaling in a rodent model of severe TBI. Severe TBI models were established using weight‐drop plus blood loss reinfusion model. Selective STING agonist ADU‐S100 or antagonist C‐176 was given as a single dose after modeling. Further, NLRP3 inhibitor MCC950 or activator nigericin, or caspase‐1 inhibitor VX765, was given as an intracerebroventricular injection 30 min before modeling. After that, a novel object recognition test, open field test, force swimming test, western blot, and immunofluorescence assays were used to assess behavioral and pathological changes in severe TBI. Administration of C‐176 alleviated TBI‐induced cognitive dysfunction and emotional impairments, neuronal loss, and inflammatory activation of glia cells. However, the administration of STING agonist ADU‐S100 exacerbated TBI‐induced behavioral and pathological changes. In addition, STING activation exacerbated pyroptosis‐associated neuroinflammation via promoting glial activation, as evidenced by increased cleaved caspase‐1 and GSDMD N‐terminal expression. In contrast, the administration of C‐176 showed anti‐pyroptotic effects. The neuroprotective effects of C‐176 were partially reversed by the NLRP3 activator, nigericin. Collectively, glial STING is responsible for neuroinflammation post‐TBI. However, pharmacologic inhibition of STING led to a remarkable improvement of neuroinflammation partly through suppressing NLRP3 signaling. The STING–NLRP3 signaling is a potential therapeutic target in TBI‐induced neurological dysfunction.

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