Inflammation plays a critical role in vertebral fractures. However, there is a lack of sufficient evidence regarding the prognostic significance of the systemic immuno-inflammatory index (SII), a novel marker of systemic inflammation, in patients with vertebral fractures. In this study, we aimed to assess the predictive value of SII in critically ill patients with vertebral fractures. The data were from the Medical Information Mart for Intensive Care III (MIMIC-III) version 1.4 and Wenzhou Hospital of Traditional Chinese Medicine. The cutoff values for SII were determined using the receiver operating characteristic curve, and the subjects were grouped accordingly. The clinical outcome measured was mortality within 30 days, 90 days, or 1 year. The following formula was used to calculate the SII: SII = (platelet count) × (neutrophil count)/ (lymphocyte count). Cox proportional-hazard models were employed to assess the relationship between SII and survival. Additionally, propensity score matching analysis and COX models were utilized to examine the association between SII and survival outcomes. The Pearson correlation test confirmed the correlation between SII and vertebral T-values measured by bone mineral density and pain indicator. A total of 354 patients were finally included from MIMIC-III in the univariate analysis, for the 30-day mortality, SII ≥ 3164 group, the hazard ratio (HR) (95% confidence interval) was 1.71 (1.01, 2.94). After adjusting for age, gender, race, anion gap, creatinine, systolic blood pressure (SBP), DBP MBP, SOFA, acute physiologic score III, chronic kidney disease, and SAPS II, SII ≥ 3164 was found to be an independent significant risk factor for death in patients (HR = 1.85, 95% CI: 1.06–3.24, P = .0315). A similar trend was observed for 90-day mortality and 1-year mortality. Propensity scores matching analysis further confirmed the association of SII and the prognosis of patients. Our validation results were consistent with it. Besides, the Pearson correlation test confirmed a significant correlation between SII and vertebral T-values measured by bone mineral density and pain indicator. The study findings revealed that SII is an independent predictor of mortality in patients with vertebral fractures. This indicates that SII can serve as a reliable and easily accessible prognostic indicator for newly diagnosed critically ill patients with vertebral fractures.