Yi Chen,1 Lu Han,1 De-Sheng Zhu,1,2 Yang-Tai Guan1,3 1Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People’s Republic of China; 2Department of Neurology, Baoshan Branch, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200444, People’s Republic of China; 3Department of Neurology, Punan Hospital, Shanghai, 200125, People’s Republic of ChinaCorrespondence: Yang-Tai Guan; De-Sheng Zhu, Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, No. 160, Pujian Road, Shanghai, 200127, People’s Republic of China, Tel +86-13386271865 ; +86-13564719779, Fax +86-21-68383482, Email yangtaiguan@sina.com; deshengzhu2008@sina.comAbstract: Stroke remains a leading cause of death and disability worldwide. Recent evidence suggests that stroke pathophysiology extends beyond vascular dysfunction to include complex interactions within the neurovascular unit (NVU), particularly involving fibrinogen. This blood-derived protein accumulates in the brain following blood-brain barrier (BBB) disruption and plays crucial roles in neuroinflammation and tissue repair. Through its unique structural domains, fibrinogen interacts with multiple cellular components, including astrocytes, microglia, and neural stem cells, thereby modulating inflammatory responses and neural repair mechanisms. This review examines fibrinogen’s structure and its diverse functions in stroke pathophysiology, focusing on its interactions with vascular cells, glial cells, and peripheral immune cells. We also discuss emerging therapeutic strategies targeting fibrinogen-mediated pathways and the challenge of translating experimental results into effective clinical treatments. Keywords: fibrinogen, neuroinflammation, stroke, neurovascular unit, neurological disorders