Functionality of the fibrinolytic system is based on activity of its central enzyme, plasmin, responsible for the removal of fibrin clots. Besides the hemostasis, fibrinolytic proteins are also involved in many other physiological and pathological processes, including immune response, extracellular matrix degradation, cell migration, and tissue remodeling. Both the impaired and enhanced activity of fibrinolytic proteins may result in serious physiological consequences: prothrombotic state or excessive bleeding, respectively. However, current medicine offers very few options for treating fibrinolytic disorders, particularly in the case of plasmin inhibition. Although numerous attempts have been undertaken to identify natural or to develop engineered fibrinolytic system modulators, structural similarities within serine proteases of the hemostatic system and pleiotropic activity of fibrinolytic proteins constitute a serious problem in discovering anti- or profibrinolytic agents that could precisely affect the target molecules and reduce the risk of side effects. Therefore, this review aims to present a current knowledge of various classes of natural inhibitors and stimulators of the fibrinolytic system being well-defined low-molecular plant secondary metabolites or constituents of plant extracts as well as plant peptides. This work also discusses obstacles caused by low specificity of most of natural compounds and, hence, outlines recent trends in studies aimed at finding more efficient modulators of plasmin activity, including investigation of modifications of natural pharmacophore templates.