This study aimed to assess the correlation between neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and systemic immunoinflammatory index (SII) levels, and short-term prognosis in patients with acute ischemic stroke (AIS) undergoing intravenous thrombolysis with alteplase (rt-PA), and to develop a nomogram model for short-term prognosis prediction. The study collected data from cases of first-episode ischemic stroke treated with intravenous thrombolysis at Wuxi People’s Hospital. Patients were categorized into either a poor prognosis group (n = 78) or a good prognosis group (n = 119) based on the modified Rankin Rating Scale score 30 days post-treatment. The results showed that peripheral blood levels of NLR, PLR and SII were significantly elevated in the poor prognosis group compared to the good prognosis group (p < 0.05). Receiver operating characteristic (ROC) curve analysis revealed that the area under the curves (AUC) of NLR, PLR and SII for predicting poor prognosis of intravenous thrombolytic therapy in AIS patients were 0.674, 0.770 and 0.779, respectively. Multivariate regression analysis identified blood glucose concentration, pre-thrombolysis National Institutes of Health Stroke Scale (NIHSS) score, prothrombin time (PT), activated partial thromboplastin time (APTT), and SII as independent influencing factors for poor prognosis of intravenous thrombolytic therapy in AIS patients (p < 0.05). A nomogram model based on these seven independent influencing factors yielded an AUC of 0.929, with calibration curve and Hosmer-Lemeshow test (χ2 = 2.654, p = 0.954) confirming the model’s good fit. Decision analysis curves demonstrated the clinical benefit of utilizing predictive models in aiding clinical decision-making. In conclusion, peripheral blood systemic inflammatory marker SII was identified as a risk factor for poor short-term prognosis in patients treated with intravenous thrombolysis. The constructed nomogram incorporating inflammatory clinical features exhibited efficient and promising clinical utility in predicting early prognosis of AIS patients treated with rt-PA thrombolysis.