Traumatic injury is a common cause of coagulopathy, primarily due to blood loss and hemodilution secondary to fluid resuscitation. Traumatic injury-associated coagulopathy often follows a course of transition from hyper- to hypocoagulable state exemplified in disseminated intravascular coagulation. The incidence of coagulopathy is significantly higher in patients with traumatic brain injury (TBI), especially those with penetrating trauma compared to injury to the trunk and limbs. This occurs despite the fact that patients with isolated TBI bleed less and receive restricted volume load of fluids. TBI-associated coagulopathy is extensively documented to associate with poor clinical outcomes, but its pathophysiology remains poorly understood. Studies in the past have shown that brain tissue is highly enriched in key procoagulant molecules. This review focuses on the biochemical and cellular characteristics of these molecules and pathways that could make brain uniquely procoagulant and prone to coagulopathy. Understanding this unique procoagulant environment will help to identify new therapeutic targets that could reverse a state of coagulopathy with minimal impacts on hemostasis, a critical requirement for neurosurgical treatments of TBI.