Objective This study aimed to investigate the role and mechanism of the histone acetyltransferase GCN5 in the pathological process following intracerebral hemorrhage (ICH). Methods A collagenase VII-S-induced rat ICH model was established, and adeno-associated virus (AAV) was used to silence GCN5 gene expression. Hematoxylin and eosin (HE) staining, immunohistochemistry, immunofluorescence, and Western blot were performed to evaluate brain tissue damage, and the expression of GCN5, hypoxia-inducible factor 1 alpha (HIF-1α), and pyroptosis-related proteins. Results The expression of GCN5 and HIF-1α was significantly elevated in the ICH model group. GCN5 knockdown notably reduced brain hemorrhage damage, and the expression of HIF-1α and pyroptosis-related proteins (NLRP3, Caspase-1, ASC, and Cleaved-GSDMD) was significantly decreased. Additionally, immunofluorescence revealed that GCN5 and HIF-1α were co-localized in brain tissues, and this co-localization was markedly diminished after GCN5 silencing.Conclusion GCN5 silencing significantly alleviates brain parenchymal damage, likely through the regulation of HIF-1α and pyroptosis-related pathways, suggesting that GCN5 may be a potential therapeutic target for ICH treatment