Objective: Glioma is the most common primary brain tumor, with a specific immune microenvironment and aggressive nature. Novel systemic immune-inflammation indices (nSII) are the most comprehensive non-invasive biomarkers that represent patients' peripheral immune status, which are urgently needed to improve clinical management. However, the diagnostic and prognostic value of nSII in glioma remains unknown. Methods: From October 2006 to April 2022, 1282 patients with primary glioma were enrolled. The preoperative peripheral blood samples were collected. Correlations between novel systemic immune-inflammation indices (nSII) and glioma grades and subtypes were analyzed using ANOVA, T-test, and ordinal logistic regression. The Cox regression model, K-M survival analysis, etc. were used to study the relationship between nSII and patients' clinical outcomes. Results: With the higher clinical grade, the percentage of NK cells increases while Th lymphocytes and T lymphocytes decrease. The percentage of NK and Th cells was also correlated with glioma subtypes. In glioblastoma patients, the higher percentage of immunoglobulin light chains was associated with a favorable prognosis, whereas the higher percentage of B lymphocytes was associated with a poor prognosis. Our study showed high diagnostic potential, eg, combined model (C4 & NK & B cells) AUC 0.879 (grade I vs IV), combined model (Th & NK & T cells) AUC 0.845 (grade II vs IV), and combined model (C4 & NK & T cells) Conclusion: The nSII can serve as a robust non-invasive diagnostic and prognostic biomarker in glioma, thus promoting clinical management in screening, stratification, and treatment optimization. This study also provides a comprehensive perspective on glioma's systemic and intracranial immune landscape, paving the way for future translational applications.