Background: Acute ischemic stroke (AIS) is the main cause of worldwide death and disability. Early neurological deterioration (END) can further increase the probability of death and disability in patients with ischemic stroke. Therefore, it is essential to find biomarkers to predict END early. Inflammatory response plays a crucial role in determining the course, outcome, and prognosis of END. Earlier studies focused on the relationship between routine hematological inflammatory markers and END, which limited the results. At present, relatively new and comprehensive markers of inflammatory response are relatively scarce. In this study, we investigate the predictive value of inflammatory markers in acute ischemic stroke cases for END which include systemic inflammatory response index (SIRI), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), and then to establish a nomogram model. Methods: A total of 375 patients with AIS were analyzed who were admitted to the Second Affiliated Hospital of Harbin Medical University from September 2019 to June 2021. The associations between END and inflammatory markers were studied by employing the analysis of univariate. Following that, through regression models of the least absolute shrinkage and selection operator, the END risk model’s feature selection was optimized. The development of the model of prediction was carried out by applying the multivariable logistic regression analysis. The calibration, discrimination, and clinical efficacy of the prediction model were studied via calibration plot, C-index, and decision curve analysis (DCA). The bootstrapping validation method was used for the evaluation of internal validation. Results: We constructed a nomogram consisting of CRP, monocytes, NIHSS and SIRI. This model had desirable calibration and discrimination, with a C-index of 0.757 (95% confidence interval: 0.702–0.805). Interval validation could still achieve the higher C-index value of 0.747. When the risk threshold for END was greater than 13% but less than 84%, DCA proved to be clinically useful. Conclusions: Our research shows that SIRI can be used as a new predictor of END, as well as a monitor of treatment response. Compared with the traditional single inflammatory indicator, the integration of SIRI nomogram can predict the occurrence of END more objectively and reliably.