Serum uric acid is reportedly associated with thrombosis development. However, still unclear is the mechanism of high uric acid in thrombosis with the involvement of let-7c. In an aim to fill this void, we conducted this study by treating mice and human umbilical vein endothelial cells with high uric acid. Analysis indicated that let-7c was upregulated in hyperuricemia patients as well as in mice and human umbilical vein endothelial cells treated with high uric acid. Furthermore, high uric acid inhibited myocyte enhancer factor-2C, but activated nuclear factor-kappa B pathway in human umbilical vein endothelial cells. Then the targeting relationship between let-7c and myocyte enhancer factor-2C was verified. On the one hand, high uric acid shortened activated partial thromboplastin time and prothrombin time of mice and declined tissue plasminogen activator level. Additionally, the treatment prolonged thrombin time and elevated the levels of thrombosis related molecules or proteins such as Fibrinogen and D-dimer. Nevertheless, these alternations could be reversed by inhibition of let-7c and nuclear factor-kappa B pathway or overexpressing myocyte enhancer factor-2C. To sum up, our results uncovered the pro-thrombotic effect of high uric acid in mice by activating myocyte enhancer factor-2C-dependent nuclear factor-kappa B pathway via let-7c upregulation.