Factor Xa and thrombin are well-known components of the coagulation cascade and have been proven to be viable targets for effective anticoagulation treatment. However, accumulating evidence suggests that these serine proteases are also crucial modulators of other cellular mechanisms through the activation of protease-activated receptor (PAR)-mediated signalling. The involvement of factor Xa, thrombin, and PARs in normal biological and pathophysiological processes has been recognized, and their potential implications have been explored in recent years. Both factor Xa and thrombin play significant roles in mediating cellular signalling effects associated with the initial development of atherosclerosis: a chronic inflammatory vascular disease. In addition, increased expression and activation of PARs may be associated with atrial fibrillation (AF) and AF-associated thromboembolism hypercoagulability. Both pathologies are associated with hypercoagulability, suggesting that the role of cellular effects of factor Xa and thrombin and of their specific inhibitors should be studied in relation to the prevention of thrombotic and pro-arrhythmic changes. This review examines the role of factor Xa-mediated and thrombin-mediated PAR activation in modulating cellular processes involved in atherosclerosis and AF and discusses the potential implication of direct factor Xa and thrombin inhibition on effects outside coagulation.