Aims.Previous findings indicate that about 50% of acute stroke patients experience hyperglycemia and is associated with unfavorable outcomes. Current treatments for acute hyperglycemia show no significant improvement in patient outcomes, indicating the ambiguity surrounding the mechanisms through with stroke triggers hyperglycemia. The purpose of this study was to explore novel biomarkers involved in the mechanism of adverse outcomes in post-stroke hyperglycemia patients. Methods.RNA sequence was performed to compare gene expression profiles between hyperglycemia and normal-glycemia stroke patients. The relationship between candidate biomarkers and adverse prognosis was validated using an enzyme-linked immunosorbent assay (ELISA) in a total of 1052 ischemic stroke patients. Results.Deferential expression gene analysis showed that neutrophil extracellular traps (NETs) could serve as a pertinent biomarker of adverse prognosis in post-stroke hyperglycemia patients. Examination of the ELISA results indicated elevated NET levels in patients with hyperglycemia and without diabetes. Multivariate analysis demonstrated that an elevated NET level was associated with a significantly increased risk of adverse outcomes at 1- and 3-months after stroke. Conclusions.Individuals without pre-existing diabetes who experienced hyperglycemia during acute ischemic stroke exhibited an elevated risk of adverse prognosis, coupled with heightened plasma levels of NETs. The connection between NET-related mechanisms and hyperglycemia in ischemic stroke patients warrants further confirmation and investigation, aiming to enhance the management of hyperglycemia post-stroke.