Thrombophilia, characterized by an imbalance between fibrinolysis and coagulation leading to inappropriate blood clotting, is a significant medical condition. The CDC has designated it as an underdiagnosed, serious, and potentially preventable disorder, contributing to an estimated 600,000–900,000 cases and 100,000 deaths annually in the United States. These figures surpass the combined annual mortality of AIDS, breast cancer, and motor vehicle accidents. The pathogenesis of thrombophilia involves complex interactions between genetic predispositions, such as mutations in Factor V Leiden, Factor II, MTHFR, and Serpine-1, and environmental factors, including unhealthy lifestyles, prolonged hospitalization, obesity, and cancer. Prevalence of specific genetic mutations varies across populations. Additional risk factors include age, family history, and pregnancy, with recent attention to increased susceptibility in SARS-CoV-2 infection. While molecular diagnostic techniques are available, there remains a need for robust, cost-effective, and accurate screening methods for large populations. This systematic review provides an updated overview of thrombophilia, encompassing pathophysiology, epidemiology, genetic and environmental risk factors, coagulation cascade, population-specific mutation prevalence, and diagnostic approaches. By synthesizing clinical and molecular evidence, this review aims to guide researchers, hematologists, and clinicians in the diagnosis and management of thrombophilia.