A proportion of acute ischemic stroke (AIS) patients suffer from early neurological deterioration (END) within 24 hours following intravenous thrombolysis (IVT), which greatly increases the risk of poor prognosis of these patients. Therefore, we aimed to explore the predictors of early neurological deterioration of ischemic origin (ENDi) in AIS patients after IVT and develop a nomogram prediction model. This study collected 244 AIS patients with post-thrombolysis ENDi as the derivation cohort and 155 patients as the validation cohort. To establish a nomogram prediction model, risk factors were identified by multivariate logistic regression analysis. The results showed that neutrophil to lymphocyte ratio (NLR) (OR 2.616, 95% CI 1.640-4.175, P < 0.001), mean platelet volume (MPV) (OR 3.334, 95% CI 1.351-8.299, P = 0.009), body mass index (BMI) (OR 1.979, 95% CI 1.285-3.048, P = 0.002) and atrial fibrillation (AF) (OR 8.012, 95% CI 1.341-47.873, P = 0.023) were significantly associated with ENDi. The area under the curve of the prediction model constructed from the above four factors was 0.981 (95% CI 0.961-1.000) and the calibration curve was close to the ideal diagonal line. Therefore, this nomogram prediction model exhibited good discrimination and calibration power and might be a reliable and easy-to-use tool to predict post-thrombolysis ENDi in AIS patients.