Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and disability rates, and long-term outcomes among survivors remain unpredictable due to the lack of reliable biomarkers. In this study, spatial transcriptomics was used to analyze molecular profiles in autopsy brain tissues from chronic ICH patients, revealing distinct transcriptomic features in the thalamus and cortex, with common inflammatory characteristics such as gliosis, apoptosis, and immune activation. Serine proteinase inhibitor NA3 (SERPINA3) was significantly upregulated in both regions and co-expressed with astrocytes in the thalamus. Pathological studies in postmortem human tissues and mouse models confirmed elevated SERPINA3 expression, with murine Serpina3n showing a similar pattern in mice. Plasma analysis of 250 ICH patients and 250 healthy controls revealed significantly higher SERPINA3 levels in ICH patients, correlating with hemorrhage severity, National Institutes of Health Stroke Scale (NIHSS), and Glasgow Coma Scale (GCS) scores, and long-term functional outcomes. Higher SERPINA3 levels within 72 hours of hemorrhage onset were independently associated with worse functional recovery (mRS ≥ 3) and increased all-cause mortality at 6 and 12 months. Additionally, SERPINA3 levels at 7 days post-ictus correlated with white matter hyperintensities and poor cognitive performance at 6 months. These findings highlight SERPINA3 as a potential prognostic biomarker for ICH, warranting further investigation into its role in long-term neurological dysfunction and validation in larger prospective cohorts.