Glioma is a malignancy with the highest mortality in central nervous system disorders. Here, we implemented the computational tools based on CRISPR/Cas9 to predict the clinical outcomes and biological characteristics of low-grade glioma (LGG). The transcriptional expression profiles and clinical phenotypes of LGG patients were retrieved from The Cancer Genome Atlas and Chinese Glioma Genome Atlas. The CERES algorithm was used to screen for LGG-lethal genes. Cox regression and random survival forest were adopted for survival-related gene selection. Nonnegative matrix factorization distinguished patients into different clusters. Single-sample gene set enrichment analysis was employed to create a novel CRISPR/Cas9 screening potential index (CCSPI), and patients were stratified into low- and high-CCSPI groups. Survival analysis, area under the curve values (AUCs), nomogram, and tumor microenvironment exploration were included for the model validation. A total of 20 essential genes in LGG were used to classify patients into two clusters and construct the CCSPI system. High-CCSPI patients were associated with a worse prognosis of both training and validation set ( < 0.0001) and higher immune fractions than low-CCSPI individuals. The CCSPI system had a promising performance with 1-, 3-, and 5-year AUCs of 0.816, 0.779, 0.724, respectively, and the C-index of the nomogram model reached 0.743 (95% CI = 0.725-0.760). Immune-infiltrating cells and immune checkpoints such as PD-1/PD-L1 and POLD3 were positively associated with CCSPI. In conclusion, the CCSPI had prognostic value in LGG, and the model will deepen our cognition of the interaction between the CNS and immune system in different LGG subtypes.