While the rate of smoking has been on the decline, the popularity of other forms of tobacco, including hookah/waterpipe continues to rise. While hookahs are thought to be safe, our recent studies have documented that exposure to waterpipe smoke (WPS) produces detrimental cardiovascular health effects, including thrombotic events; similar to what was observed with traditional cigarette smoking. In this connection, we have also documented that the new risk, termed thirdhand smoke (THS)-which is the residual tobacco smoke contaminant that remains after a cigarette is extinguished- increases the risk of thrombosis, much like both active/first hand smoke (FHS) and passive/second hand smoke (SHS) exposure. However, whether Thirdhand Hookah Smoke (THHS) exposure produces similar negative health effects remains to be determined. By employing a novel exposure protocol, mice were exposed to THHS starting at 10 weeks of age for three months, as per the golad standard Beirut protocol, which is as follows: one-hour session of 171 puffs of 530 mL volume, each puff is 2.6 s duration, and there are a 17 s interpuff interval. Our data shows that THHS exposed platelets exhibited enhanced agonist-induced aggregation, as well as dense and alpha granules secretion responses. Moreover, we also found that integrin activation, and phosphatidylserine exposure are increased as a result of THHS exposure. Consistent with these findings, we also obtained biochemical evidence of enhanced platelet reactivity, namely increased activation/phosphorylation of Akt. Notably, we observed high levels of the tobacco marker cotinine in the urine of the THHS mice, but not from the controls. Finally, and in terms of its in vivo impact, we observed that THHS enhances hemostasis and increases the risk of thrombosis in comparison to controls as documented by the shortened bleeding and occlusion times. Our results demonstrate, for the first time, that exposure to THHS results in a prothrombotic phenotype, which is attributed, at least in part, to a potentiated state of platelet reactivity. Thus, the negative health consequences of THHS should not be underestimated, and warrant further investigation. These findings should also guide policy development for regulating exposure to this form of tobacco.