Background: Patients who have suffered an acute ischemic stroke (AIS) and are smokers may have a better outcome following thrombolytic therapy when compared with non-smokers. While this finding is controversial, data on baseline clinical risk factors to predict treatment efficacy of thrombolytic therapy using ambulatory status in patients who suffered AIS and are smokers is not common. Methods: Between 2010 and 2016, retrospective data on patients who have suffered an AIS and received recombinant tissue plasminogen activator (rtPA) were obtained from Greenville health system registry. Assessment of clinical risk factors and the likelihood of an improvement in post-stroke ambulation among smokers and non-smokers was carried out using multivariate logistic regression. Results: Of 1001 patients, 70.8% were smokers and 29.2% non-smokers. Among the smokers and non-smokers, 74.6% and 84.6% improvement in ambulation respectively at discharge. The odds of improved ambulation decrease among smokers as age group increases compared to those below 50 [(60–69 years, aOR, 0.30, 95% C.I, 0.108–0.850, p < 0.05), (70–79 years aOR, 0.27, 95% C.I, 0.096–0.734, p < 0.05), (80+ years aOR, 0.16, 95% C.I, 0.057–0.430, P < 0.01). Patients with National Institute of Health Stroke Scale Score (NIHSS) score > 7 (reference <7) were 91% less likely to have improved ambulation among smokers and non-smokers (aOR, 0.09, 95% C.I, 0.055–0.155, P = 0.01), and (aOR, 0.08, 95% C.I, 0.027–0.214, P = 0.01) respectively. Atrial fibrillation was an independent predictor of decreased improvement in ambulation only among smokers (aOR, 0.58, 95% C.I, 0.356–0.928 P < 0.05). Conclusion: Our findings suggest that elderly smokers with atrial fibrillation would benefit more from aggressive management of atrial fibrillation than non-smokers.