Brilliant blue G, a selective P2X7 receptor antagonist, exhibits neuroprotective properties. This study examined whether brilliant blue G treatment ameliorates early brain injury after experimental subarachnoid hemorrhage, specifically via inhibiting p38 mitogen-activated protein kinase-related proapoptotic pathways. Controlled in vivo laboratory study. Animal research laboratory. One hundred fifty-four adult male Sprague-Dawley rats weighing 280-320 g. Subarachnoid hemorrhage was induced in rats by endovascular perforation. Experiment 1 implemented sham-operated rats (sham) and subarachnoid hemorrhage animals, which received vehicle (subarachnoid hemorrhage + vehicle), brilliant blue G (subarachnoid hemorrhage + brilliant blue G), or brilliant blue G plus 2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate (BzATP) (subarachnoid hemorrhage + brilliant blue G + BzATP). The animals were intraperitoneally treated with brilliant blue G (30 mg/kg) at 30 minutes after subarachnoid hemorrhage. BzATP (50 μg/rat), a P2X7 receptor agonist, was intracerebroventricularly administered. Experiment 2 implemented sham-operated rats (sham) and subarachnoid hemorrhage animals, which received vehicle (subarachnoid hemorrhage + vehicle), scramble small interfering RNA (subarachnoid hemorrhage + scramble small interfering RNA), or P2X7 receptor small interfering RNA (subarachnoid hemorrhage + P2X7 receptor small interfering RNA). Subarachnoid hemorrhage grading, neurobehavioral score, and brain edema were evaluated at 24 and 72 hours after surgery. The expression of phosphorylated p38 mitogen-activated protein kinase, phosphorylated extracellular signal-regulated kinases, phosphorylated c-Jun N-terminal kinases, P2X7 receptor, Bcl-2, and cleaved caspase-3 in the left cerebral hemisphere were determined by Western blot. Neuronal apoptosis was examined by double immunofluorescence staining using P2X7 receptor, terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling, and neuronal nuclei. Brilliant blue G significantly improved neurobehavioral function and ameliorated brain water content at 24 and 72 hours after subarachnoid hemorrhage. BzATP reversed these treatment effects. Brilliant blue G attenuated neuronal apoptosis in the subcortex, which was associated with decreased expression of phosphorylated p38 mitogen-activated protein kinase and cleaved caspase-3 and an increased expression of Bcl-2 in the left cerebral hemisphere. The beneficial effects of P2X7 receptor small interfering RNA were also mediated by a p38 mitogen-activated protein kinase pathway. Inhibition of P2X7 receptor by brilliant blue G or P2X7 receptor small interfering RNA can prevent early brain injury via p38 mitogen-activated protein kinase after subarachnoid hemorrhage.