PURPOSE: Intracerebral hemorrhage (ICH) is a life-threatening subtype of stroke, and neuroinflammation is a key factor in brain injury after ICH. Spermidine (SPD), a natural polyamine existing in all eukaryotic cells, has exerted beneficial effects such as anti-inflammation and anti-oxidation in many disease models. However, its effects and mechanisms in ICH remain unclear. This study aims to investigate the therapeutic potential of SPD in the ICH model. METHODS AND MATERIALS: In the in vivo experiments, C57BL/6 mice were randomly divided into three groups (Sham group, ICH + vehicle group, and ICH + SPD group). ICH was induced by collagenase VII and SPD (15 mg/kg) was administered intraperitoneally at 6, 30, and 54 hours post-ICH. Then the mice were euthanized on the third day for further experiments: Western blot, immunofluorescence staining, immunohistochemical staining, Evans blue extravasation, TUNEL staining, brain water content measurement and behavioral tests. In in vitro experiments, BV2 cells were stimulated with hemin for 24 hours to mimic ICH. Western blot and ELISA were used to assess inflammatory response of microglia. RESULTS: The results of animal experiments showed that SPD dramatically reduced hematoma volume, area of brain injury, brain cell death, and significantly improved neurological deficits compared with the ICH + vehicle group. Furthermore, SPD suppressed the activated microglia/macrophages, infiltrated neutrophils and the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α), alleviated blood-brain barrier (BBB) damage, and reduced brain water content in vivo. In cell experiments, the results indicated that SPD (8 μM/L) suppressed the expression of CD32 and iNOS and the release of inflammatory factors (IL-1β, IL-6, and TNF-α). CONCLUSION: These findings indicate the neuroprotective role of SPD in the ICH model in mice, which is likely to be associated with inhibition of neuroinflammation and protection of the BBB.