The hemostatic system (HS) is crucial for human survival, both by preventing excessive bleeding and also through close links to the immune system. Both systems cooperate to defend us from attacks by microorganisms and viruses. However, the behavior of the HS changes radically in the presence of cancer, becoming its powerful ally. Excessive individual responses of the HS to sepsis or virus attacks also require further investigation. The current review aims to explain the main pathophysiological mechanisms responsible for the behaviors of the HS in inflammation and cancer. We address the three main components of the HS, i.e., platelets, blood coagulation, and fibrinolysis, separately, and provide detailed information on their different activities in relation to inflammation and cancer. A better understanding of the mechanisms underlying the HS may help to improve daily clinical practice. This review also considers the possible roles of anticoagulant and antifibrinolytic drugs in counteracting the abnormal reactions of the HS during the course of infectious diseases and cancer. Further ad hoc studies are needed to assess if these drugs can reverse or at least reduce the adverse impacts of the HS in infections and cancer.