Clinical data indicates that glioma patients have poor treatment outcomes and clinical prognosis. The role of olfactory signaling pathway-related genes (OSPRGs) in glioma has not been fully elucidated. In this study, we aimed to investigate the role and relationship between OSPRGs and glioma. Univariate and multivariate Cox regression analyses were performed to assess the relationship between OSPRGs and the overall survival of glioma based on public cohorts, and the target gene (G Protein Subunit Alpha L,
GNAL
) was screened. The association of
GNAL
expression with clinicopathological characteristics, gene mutation landscape, tumor immune microenvironment (TIME), deoxyribonucleic acid (DNA) methylation, and naris-occlusion controlled genes (NOCGs) was performed. Immunohistochemistry was used to evaluate GNAL level in glioma. Further analysis was conducted to evaluate the drug sensitivity, immunotherapy response, and functional enrichment of
GNAL
.
GNAL
was an independent prognostic factor, and patients with low
GNAL
expression have a poor prognosis. Expression of
GNAL
was closely associated with clinicopathological characteristics, DNA methylation, and several immune-related pathways. Immune infiltration analysis indicated that
GNAL
levels were negatively correlated with immune scores.
GNAL
low-expression group showed efficacy with anti-PD-1 therapy. Ten compounds with significantly different half-maximal inhibitory concentration (IC50) values between the
GNAL
high and low-expression groups were identified. Furthermore, its expression was associated with several immune cells, immune-related genes, and NOCGs. The expression of
GNAL
is closely associated with clinicopathological characteristics, TIME, and the response to therapeutic interventions, highlighting its potential as a prognostic biomarker for glioma.