Thrombo-embolic ischemic stroke is a serious and debilitating disease, and it remains the second most common cause of death worldwide. Tobacco smoke exposure continues to be responsible for preventable deaths around the world, and is a major risk factor for stroke. Platelets play a fundamental role in clotting, and their pathophysiological functioning is present in smokers and stroke patients, resulting in a pro-thrombotic state. In the current manuscript, atomic force and scanning electron microscopy were used to compare the platelets of smokers, stroke patients and healthy individuals. Results showed that the elastic modulus of stroke platelets is decreased by up to 40%, whereas there is an elasticity decrease of up to 20% in smokers' platelets. This indicates a biophysical alteration of the platelets. Ultrastructurally, both the stroke patients and smokers' platelets are more activated than the healthy control group, with prominent cytoskeletal rearrangement involved; but to a more severe extent in the stroke group than in the smokers. Importantly, this is a confirmation of the extent of smoking as risk factor for stroke. We conclude by suggesting that the combined AFM and SEM analyses of platelets might give valuable information about the disease status of patients. Efficacy of treatment regimes on the integrity, cell shape, roughness and health status of platelets may be tracked, as this cell's health status is crucial in the over-activated coagulation system of conditions like stroke.