Oxidative stress and neuroinflammation are important secondary injury mechanisms in intracranial hemorrhage (ICH). V-set and immunoglobulin domain-containing 4 (VSIG4) has an inhibitory effect on oxidative stress and the inflammatory response. This study aimed to explore the possible role of VSIG4 in ICH-related neuropathology.In this study, VSIG4 levels were investigated in an ICH mouse model and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Moreover, we examined oxidative stress levels, pro-inflammatory cytokine production, neuronal damage, inflammatory cell activation, brain water content, and neurological function. We performed these assays in ICH mice and macrophages with different VSIG4 levels. Additionally, the critical role of the nuclear factor erythroid 2 related factor 2/heme oxygenase-1 (NRF2/HO-1) signaling pathway in VSIG4 function was verified.VSIG4 ameliorated neurological deficits in ICH mice ( < 0.01), alleviated cerebral edema ( < 0.05), and increased glutathione ( < 0.05) and decreased superoxide dismutase (SOD) levels ( < 0.01) in the perihematomal area and LPS-stimulated RAW264.7 cells. It also reduced Malondialdehyde (MDA) accumulation ( < 0.01), alleviated oxidative stress, and decreased interleukin-1β (IL-1β) ( < 0.01) and tumor necrosis factor-alpha (TNF-α) levels ( < 0.01), thereby attenuating the inflammatory response. Additionally, treatment of LPS-stimulated RAW264.7 cells with VSIG4 resulted in less damage to HT22 cells ( < 0.05). To further validate the involvement of the NRF2/HO-1 pathway in VSIG4-mediated neuroprotection, brusatol (an NRF2 inhibitor) was administered.Our study demonstrates the neuroprotective effect and mechanism of action of VSIG4 in ICH.