AimTo develop and validate a novel weighted score integrating multisystem laboratory and clinical variables to predict poor 3‐month outcome (mRS score of 3–6) in acute ischemic stroke (AIS) patients with intravenous thrombolysis (IVT) therapy.MethodsWe retrospectively analyzed data from Trial of Revascularization Treatment for Acute Ischemic Stroke study. The Supra‐Blan2t score was derived using the data on age, the National Institutes of Health Stroke Scale score, history of atrial fibrillation, blood sugar level, neutrophil count, direct bilirubin level, platelet–lymphocyte ratio, and TnI level in the derivation cohort of 433 patients, and validated in a cohort of 525 patients. Furthermore, we compared the performance of the Supra‐Blan2t score with DRAGON, TURN, and SPAN‐100 scores.ResultsThe discrimination capacity in the derivation and validation cohorts was good for poor 3‐month outcome (the area under the curve was 0.821 and 0.843, respectively). The cumulative incidence of poor 3‐month outcome significantly increased across risk categories in the derivation (low‐risk, 9.2%; medium‐risk, 17.4%; and high‐risk, 58.8%) and validation cohorts (12.7%, 36.5%, and 73.6%, respectively). The performance of the Supra‐Blan2t score was similar to or superior to DRAGON, TURN, and SPAN‐100 scores.ConclusionThe Supra‐Blan2t score, based on easily available multisystem laboratory and clinical variables, reliably predicted poor 3‐month functional outcome in AIS patients treated with IVT therapy featuring good calibration and discrimination.