Phenotypic switching in vascular smooth muscle cells (VSMCs) is key to the formation and progression of intracranial aneurysms (IAs). High-mobility group box 1 (HMGB1), a damage-associated molecule, significantly influences the progression of various diseases. Ferroptosis is an iron-dependent cell death process that is controlled by extensive membrane damage induced by lipid peroxidation. However, few studies have investigated the associations between VSMCs, HMGB1, ferroptosis, and IAs. To analyze the associations between VSMCs, HMGB1, ferroptosis, and IAs, we collected human tissue and blood samples, established an oxidative damage model in VSMCs induced using hydrogen peroxide, and analyzed the effects of interventions related to ferroptosis and HMGB1 on VSMC phenotypic changes in vitro. We measured ferroptosis levels, proliferation, migration capacity, and inflammatory molecule expression in VSMCs. In addition, we analyzed the nuclear-cytoplasmic translocation of HMGB1 and the nuclear factor κ light chain-enhancer of activated B cells (NF-κB) protein subunit p65. Then, we investigated the effects of HMGB1 inhibition on IA formation and progression in an elastase-induced rat model. Clinical experiments using human samples confirmed significant correlations between VSMC phenotypic switching, HMGB1, ferroptosis, and IAs. HMGB1 was activated and underwent translocation from the nucleus to the cytoplasm under oxidative stress conditions. By binding to TLR4, HMGB1 activated the NF-κB p65 pathway, promoted NF-κB p65 nuclear translocation, and induced inflammatory responses and ferroptosis, thereby mediating VSMC phenotypic switching. In animal studies, HMGB1 inhibition markedly reduced IA formation and progression. HMGB1 regulates VSMC phenotypic switching and contributes to the development of IAs by mediating ferroptosis.