Hypertension is a risk factor for vascular injury and thrombotic complications, and smoking tobacco is a risk factor for the development and exacerbation of hypertension. The influence of waterpipe smoke (WPS) on coagulation and vascular injury in hypertension is not fully understood. Here, we evaluated the effects of WPS in mice made hypertensive (HT) by infusing angiotensin II (Ang II) for 42 days. On day 14 of the infusion of Ang II or vehicle (normotensive; NT), mice were exposed either to air or WPS for four consecutive weeks. Each session was 30 min/day for 5 days/week. The concentrations of tissue factor, von Willebrand factor, fibrinogen, and plasminogen activator inhibitor-1 were elevated in the HT + WPS group versus either HT + air or NT + WPS groups. Similarly, in the HT + WPS group, thrombogenicity was increased both in vivo and in vitro, compared with either HT + air or NT + WPS groups. In aortic tissue, adhesion molecules including P-selectin, E-selectin, intercellular adhesion molecule-1, and vascular adhesion molecule-1 were increased in the HT + WPS group versus the controls. Likewise, various proinflammatory cytokines and markers of oxidative stress augmented in the HT + WPS group compared with either HT + air or NT + WPS. DNA damage, cleaved caspase-3, and cytochrome C were increased in the HT + WPS group versus the controls. The immunohistochemical expression of nuclear factor erythroid 2-related factor 2 was increased in the HT + WPS group versus either HT + air or NT + WPS. Taken together, our findings show that WPS exposure intensified thrombogenicity and vascular damage in experimentally induced hypertension. Our data suggest that vascular toxicity of WPS may be exaggerated in hypertensive patients.