Background <p>Modulating harmful neuroimmune responses is a promising therapeutic approach for hemorrhagic stroke, a condition that still lacks effective treatment. The immune checkpoint B and T Lymphocyte Attenuator (BTLA) helps suppress immune activation; however, its role in intracerebral hemorrhage (ICH) remains unclear. This study explores whether a BTLA-activating antibody can reduce neuroinflammation, mitigate brain injury, improve recovery after ICH, and elucidate the underlying mechanisms.</p> Methods <p>An ICH model was generated in male C57BL/6 mice by stereotactic injection of collagenase VII-S into the left striatum. The mice received intraperitoneal administration of an agonistic anti-BTLA antibody to serve as a BTLA agonist. Therapeutic effects were evaluated using a multimodal approach that included flow cytometry, Western blotting, immunofluorescence staining, histological examination, and behavioral tests. Additionally, microglial depletion was performed by feeding the CSF1R inhibitor PLX5622.</p> Results <p>Our findings demonstrate that a single dose of an agonistic anti-BTLA antibody, administered 30&#xa0;min post-ICH, significantly reduced the infiltration of CD45^high, CD3⁺, and CD3⁺CD4⁺ immunocytes, as well as the activation of CD3⁺CD4⁺ and CD3⁺CD8⁺ immunocytes, in the hemorrhagic brain following acute ICH. Simultaneously, it reduced neutrophil infiltration into the hemorrhagic brain and suppressed the activation of peripheral CD3⁺CD8⁺ immune cells. It also alleviated molecular and cellular neuroinflammation in the hemorrhagic brain during the early phase after ICH. These effects in the brain of adult male mice ultimately reduced both acute-phase brain injury volume and long-term residual lesions, while facilitating neurological recovery. However, microglial depletion abolished the anti-inflammatory effects of the agonistic anti-BTLA antibody, indicating that its action is contingent on microglia-mediated immunomodulation.</p> Conclusion <p>The agonistic anti-BTLA antibody significantly attenuates neuroinflammation and reduces brain injury following ICH, accompanied by enhanced neurological recovery. This protective effect appears to be mediated through microglia-dependent mechanisms. Our findings highlight BTLA may be a novel and promising immunomodulatory target for the treatment of ICH.</p> Graphical Abstract <p></p>