Background Hyperglycemia has been associated with adverse outcomes in patients with acute ischemic stroke ( AIS ) and may influence outcomes after tissue plasminogen activator ( tPA ). We sought to analyze the association of acute and chronic hyperglycemia on clinical outcomes in tPA‐ treated patients. Methods and Results We identified 58 265 AIS patients from 1408 sites who received tPA from 2009 to 2013 in Get With The Guidelines‐Stroke. Acute hyperglycemia at admission was defined as a plasma glucose level >140 mg/dL. Chronic hyperglycemia was defined by plasma glycosylated hemoglobin (HbA1c) >6.5%. Post‐ tPA outcomes were analyzed using logistic regression. Blood glucose >140 mg/dL and HbA1c >6.5 were associated with worse clinical outcomes (symptomatic intracranial hemorrhage [ sICH ], life‐threatening hemorrhage, and in‐hospital mortality and length of stay) in diabetic and nondiabetic patients. Among patients with documented history of diabetes, increasing admission glucose up to 200 mg/dL was associated with increased adjusted odds ratio ( aOR ) of in‐hospital mortality ( aOR, 1.07) and sICH ( aOR, 1.05) per 10 mg/dL increase in blood glucose. Increasing HbA1C to 8% was associated with increased odds of in‐hospital mortality ( aOR, 1.19) and sICH ( aOR, 1.16) per 1% increase in HbA1c. Similar findings were observed in patients without a documented history of diabetes. There was no further increase in poor outcomes above the blood glucose level of 200 mg/dL or HbA1c >8. Conclusion Acute and chronic hyperglycemia are both associated with increased mortality and worse clinical outcomes in AIS patients treated with tPA . Controlled trials are needed to determine whether acute correction of hyperglycemia can improve outcomes after thrombolysis.