Sickle cell disease (SCD), a genetic disorder affecting millions globally, is characterized by hemoglobin polymerization in red blood cells (RBCs), leading to sickling, chronic hemolysis, and systemic vascular injury. While microvascular complications are well-documented, arterial pathologies pose significant, understudied risks, including early-onset strokes, osteonecrosis, ischemic priapism, and nephropathy. Unlike atherosclerosis, which develops over decades via lipid-driven plaque formation, SCD arteriopathy arises from rigid RBC-induced hemodynamic changes, chronic inflammation, and proteolytic degradation of arterial elastin and collagen. This results in artery wall thinning, altered arterial compliance, and endothelial dysfunction that predisposes patients to life-threatening complications. Hemodynamic forces, uniquely perturbed in SCD due to abnormal blood rheology and RBC adhesion, play a central role in arterial damage. Advanced biomedical engineering tools and computational fluid dynamics (CFD) reveal how altered shear stress, flow disturbances, and cellular aggregation exacerbate structural changes. Advanced CFD models can integrate biological factors to predict sites of occlusion and potentially guide therapeutic strategies. This chapter describes cardiovascular biomechanics and clinical insights to unravel SCD-specific arteriopathy mechanisms. By bridging hematological abnormalities with hemodynamic perturbations and tissue-level remodeling, this chapter highlights interdisciplinary approaches to mitigate arterial complications, offering new avenues for early intervention and personalized care in this vulnerable population.