Hemostasis is the most important protective mechanism for human survival following harmful vascular damage caused by internal disease or external injury. Physiological mechanism of hemostasis is partially understood. Hemostasis can be initiated by either intravascular injury or external bodily injury involving two different levels of damage [i.e., limited to the endothelium or combined with extravascular tissue (EVT)]. In intravascular injury, traumatic damage limited to local endothelium typically is of no consequence, but disease-induced endothelial damage associated with systemic endothelial injury seen in sepsis and other critical illnesses could cause generalized ‘endotheliopathy’. It triggers no bleeding but promotes serious endothelial molecular response. If intravascular local trauma extends beyond the endothelium and into EVT, it causes intravascular ‘bleeding’ and initiate ‘clotting’ via normal hemostasis. In external bodily injury, local traumatic damage always extends to the endothelium and EVT, and triggers ‘bleeding’ and ‘clotting’. Systemic endotheliopathy activates only unusually large von Willebrand factor multimers (ULVWF) path and mediates ‘microthrombogenesis’, producing ‘microthrombi’ strings. This partial activation of hemostasis with ULVWF path leads to vascular microthrombotic disease. But localized traumatic injury extending to the endothelium and EVT activates both ULVWF and tissue factor paths. Combined activation of ULVWF and tissue factor paths provides normal hemostasis in external bodily injury, but causes ‘macrothrombus’ formation in intravascular injury. This ‘two-path unifying theory’ concept succinctly elucidates simplified nature of hemostasis in intravascular and external bodily injuries. It also clarifies different pathogenesis of every hemorrhagic disease and thrombotic disorder related to internal vascular disease and external vascular injury.