Background: Squamous cell carcinoma (SCC) accounts for around 90% of malignant neoplasms of the oral cavity and is a serious public health problem. The 5-year survival rate of oral and pharyngeal SCC is estimated to be around 63%, despite advances in the treatments. Particularly SCCs affecting the oral and mobile portion of the tongue (OTSCCs) show a high pitfall of recurrence and lymph node metastasis. Within this context, biomarker studies are essential for better understanding of the pathogenesis of the disease, better prognostication and better therapeutic strategies. Proteins of the plasminogen activator system (PAS) have been correlated with the prognosis and clinical behavior of several types of cancer, such as breast, lung, esophageal, gastric, and oral cancers. The PAS consists of a set of molecules that integrates extracellular matrix (ECM) changes. Within this system, conversion of the pro-enzyme plasminogen into plasmin occurs, cleavage of ECM, and stimulation of other proteolytic enzymes as matrix metalloproteinases (MMPs). In malignant neoplasms, the conversion of plasminogen to plasmin is intermediated principally by urokinase-type plasminogen activator (uPA). The formation of plasmin is blocked basically by plasminogen activator inhibitor-1 (PAI-1, also called SERPINE-1). Although, the main function of PAI-1 is the regulation of the PAS, it also shares in alternate biological processes implicated in tumorigenesis. Aim of the Study: This review discusses the role of PAI-1 in inhibiting fibrinolysis in oral cancer and its potential as a biomarker and therapeutic target.