Sickle cell disease, the most common genetic blood disorder in the world, has high clinical variability, negatively impacts quality of life and contributes to early mortality. Sickled erythrocytes cause blood flow obstruction, hemolysis, and several hemostatic changes that promote coagulation. These events, in turn, induce chronic inflammation, characterized by elevated plasma levels of pro-inflammatory markers, which aggravates the already unfavorable state of the circulatory system. Empirical evidence indicates that the hemostatic and inflammatory systems continuously interact with each other and thereby further propagate the hypercoagulability and inflammatory conditions. In this review article, we discuss the pathophysiological aspects of sickle cell disease and the hemostatic and inflammatory changes that underlie its pathogenesis.