Glioblastoma (GBM) is a malignant brain tumor associated with high mortality. Long non‑coding RNAs (lncRNAs) are increasingly being recognized as its modulators. However, it remains mostly unexplored how lncRNAs are mediated by DNA methylation in GBM. The present study integrated multi‑omics data to analyze the epigenetic dysregulation of lncRNAs in GBM. Widely aberrant methylation in the lncRNA promoters was observed, and the lncRNA promoters exhibited a more hypomethylated pattern in GBM. By combining transcriptional datasets, it was possible identify the lncRNAs whose transcriptional changes might be associated with the aberrant promoter methylation. Then, a methylation‑mediated lncRNA regulatory network and functional enrichment analysis of aberrantly methylated lncRNAs showed that lncRNAs with different methylation patterns were involved in diverse GBM progression‑related biological functions and pathways. Specifically, four lncRNAs whose increased expression may be regulated by the corresponding promoter hypomethylation were evaluated to have an excellent diagnostic effect and clinical prognostic value. Finally, through the construction of drug‑target association networks, the present study identified potential therapeutic targets and small‑molecule drugs for GBM treatment. The present study provides novel insights for understanding the regulation of lncRNAs by DNA methylation and developing cancer biomarkers in GBM.