Early identification of patients at high risk of poor prognosis after thrombolytic therapy for acute ischemic stroke (AIS) is essential for optimizing clinical management. This study aimed to develop and internally validate a prognostic nomogram integrating clinical and laboratory variables. This retrospective study included 286 AIS patients treated with recombinant tissue plasminogen activator between January 2022 and August 2024. Patients were categorized into favorable (modified Rankin Scale ≤ 2, n = 198) and poor prognosis groups (modified Rankin Scale > 2, n = 88) based on outcomes at 90 days post-treatment. Clinical data, including demographic information, comorbidities, National Institutes of Health Stroke Scale (NIHSS) scores, and laboratory parameters (e.g., white blood cell [WBC] count, neutrophil count, and D-dimer levels), were collected. Multivariate logistic regression analysis identified independent predictors of poor prognosis. A nomogram was developed to predict prognosis, with performance evaluated through receiver operating characteristic analysis, Bootstrap resampling (n = 1000), and calibration curves. Clinical utility was assessed using decision curve analysis. Multivariate analysis identified 5 independent predictors of poor prognosis: diabetes (odds ratio [OR] = 6.511, 95% confidence interval [CI]: 1.667–24.605,
P
= .008), admission NIHSS score (OR = 1.354, 95% CI: 1.097–1.565,
P
= .001), WBC count (OR = 1.459, 95% CI: 1.114–1.786,
P
= .002), neutrophil count (OR = 1.402, 95% CI: 1.037–1.758,
P
= .022), and D-dimer level (OR = 2.088, 95% CI: 1.360–2.988,
P
= .001). The nomogram showed excellent discrimination (AUC = 0.896), good calibration (Hosmer–Lemeshow,
P
= .856), and clinical utility. Internal validation yielded a concordance index of 0.728. This retrospective study suggests that diabetes, NIHSS score, WBC count, neutrophil count, and D-dimer levels may be useful predictors of poor prognosis in thrombolysed AIS patients. A nomogram based on these factors showed good discriminative ability and clinical utility. Further prospective, multicenter validation is needed to confirm its applicability in routine practice.