Sickle cell disease is a genetic disease that increases systemic inflammation as well as the risk of pediatric strokes, but links between sickle-induced inflammation and arterial remodeling are not clear. Cathepsins are powerful elastases and collagenases secreted by endothelial cells and monocyte-derived macrophages in atherosclerosis, but their involvement in sickle cell disease has not been studied. Here, we investigated how tumor necrosis alpha (TNFα) and circulating mononuclear cell adhesion to human aortic endothelial cells (ECs) increase active cathepsins K and V as a model of inflammation occurring in the arterial wall. ECs were stimulated with TNFα and cultured with peripheral blood mononuclear cells (PBMCs) from persons homozygous for sickle (SS) or normal (AA) hemoglobin. TNFα was necessary to induce cathepsin K activity, but either PBMC binding or TNFα increased cathepsin V activity. SS PBMCs were unique; they induced cathepsin K in ECs without exogenous TNFα (n = 4, P < 0.05). Inhibition of c-Jun N-terminal kinase (JNK) significantly reduced cathepsins K and V activation by 60% and 51%, respectively. Together, the inflammation and activated circulating mononuclear cells upregulate cathepsin activity through JNK signaling, identifying new pharmaceutical targets to block the accelerated pathology observed in arteries of children with sickle cell disease.