Diffuse glioma, the most common intracranial malignant tumor, is characterized by immunosuppression. The prognostic significance and potential therapeutic value of SYK remain obscure. Here, we explored the performance of SYK in predicting patient outcomes and as a therapeutic target. The mRNA expression and clinical data for pancancer and normal tissues and more than 2,000 glioma samples were collected from public databases. The expression level of SYK was evaluated by qPCR and IHC. The prognostic value of SYK was assessed using the Kaplan-Meier curves and univariate and multivariate Cox regression analyses. A sequence of immune and stromal infiltration analyses was calculated based on the ESTIMATE algorithm, ssGSEA algorithm, TIMER, and single-cell analysis. The SYK-related subtypes were identified a Consensus Cluster Plus analysis. SYK was significantly differentially expressed in multiple tumors and normal tissues. Importantly, high-expression SYK was enriched in malignant phenotypes of diffuse gliomas, which was further validated by qPCR and IHC. Survival analysis uncovered that SYK was an independently unfavorable prognostic marker in diffuse glioma. Functional enrichment analysis and immune and stromal infiltration analyses showed that SYK was involved in shaping the immunosuppressive microenvironment of diffuse glioma. Additionally, SYK expression was closely associated with some immune checkpoint molecules and M2 macrophage infiltration, which was validated by IHC and single-cell analysis. Diffuse glioma with Sub1 exhibited a worse prognosis, immunosuppressive microenvironment, and higher expression of immune checkpoint genes. SYK is involved in shaping the immunosuppressive microenvironment and served as a promising prognosis biomarker and immunotherapeutic target for diffuse glioma.