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Traumatic brain injury (TBI) is one of the most common neurological disorders causing memory reduction, particularly short-term memory (STM). We showed that, during TBI-induced inflammation, increased blood content of fibrinogen (Fg) enhanced vascular protein transcytosis and deposition of extravasated Fg in vasculo-astrocyte interfaces. In addition, we found that deposition of cellular prion protein (PrP C ) was also increased in the vasculo-astrocyte endfeet interface. However, association of Fg and PrP C was not confirmed. Presently, we aimed to define whether Fg can associate with PrP C on astrocytes and cause their activation. Cultured mouse brain astrocytes were treated with medium alone (control), Fg (2 mg/mL or 4 mg/mL), 4 mg/mL of Fg in the presence of a function-blocking anti-PrP C peptide or anti-mouse IgG, function-blocking anti-PrP C peptide, or anti-mouse IgG alone. After treatment, either cell lysates were collected and analyzed via Western blot or coimmunoprecipitation was performed, or astrocytes were fixed and their activation was assessed with immunohistochemistry. Results showed that Fg dose-dependently activated astrocytes, increased expressions of PrP C and tyrosine (tropomyosin) receptor kinase B (TrkB), and PrP gene. Blocking the function of PrP C reduced these effects. Coimmunoprecipitation demonstrated Fg and PrP C association. Since it is known that prion protein has a greater effect on memory reduction than amyloid beta, and that activation of TrkB is involved in neurodegeneration, our findings confirming the possible formation of Fg-PrP C and Fg-induced overexpression of TrkB on astrocytes suggest a possible triggering mechanism for STM reduction that was seen previously during mild-to-moderate TBI. NEW & NOTEWORTHY For the first time we showed that fibrinogen (Fg) can associate with cellular prion protein (PrP C ) on the surface of cultured mouse brain astrocytes. At high levels, Fg causes upregulation of astrocyte PrP C and astrocyte activation accompanied with overexpression of tyrosine receptor kinase B (TrkB), which results in nitric oxide (NO) production and generation of reactive oxygen species (ROS). Fg/PrP C interaction can be a triggering mechanism for TrkB-NO-ROS axis activation and the resultant astrocyte-mediated neurodegeneration.