Schizophyllum commune is a widely distributed mushroom used as an herbal medicine and an ingredient in healthy food. In this study, a protease from a fermented culture broth of S. commune demonstrated strong fibrinolytic and fibrinogenolytic activities. This fibrinolytic protease showed a suppression effect in blood coagulation in co-incubation with rat citrated blood through thromboelastographic analysis. The protease suppressed aggregation of fibrin (ogen), but not the platelets, in clotting formation and significantly decreased the clot strength. We also found very little potency in this protease to activate plasminogen, thus it exhibits the potential for an ideal fibrinolytic candidate for therapeutic applications in the future.