The protein C (PC) pathway is a well-characterized anticoagulant system. Produced mainly by the liver as a zymogen, PC is activated on the vascular endothelial cell surface by thrombin–thrombomodulin complex. Once activated, PC inactivates two important cofactors of the coagulation cascade, factors Va and VIIIa, which are crucial for thrombin generation. For many years, this pathway has been studied for the clotting process, but only recently great progress has been made in understanding other functions of the PC system. Indeed, much work demonstrates that this pathway exerts several activities not only involved in the coagulative process but also in inflammation, cell proliferation, apoptosis, stabilization of endothelial barrier, and fibrinolysis. In addition, a recent study has shed light on a new role of the PC system in controlling intestinal permeability function by regulating tight junction molecules and promoting mucosal healing. This review highlights these recent insights in the context of the complex pathogenesis of inflammatory bowel disease.