Glioblastoma multiforme (GBM) is one of the most common primary malignant brain tumors in adults. Due to the poor prognosis of patients, the median survival time of GBM is often less than 1 year. Therefore, it is very necessary to find novel treatment options with a good prognosis for the treatment or prevention of GBM. In recent years, flavonoids are frequently used to treat cancer. It is a new attractive molecule that may achieve this promising treatment option. Flavonoids have been proved to have many biological functions, such as antioxidation, prevention of angiogenesis, anti-inflammation, inhibition of cancer cell proliferation, and protection of nerve cells. It has also shown the ability to regulate long non-coding RNA (LncRNA). Studies have confirmed that flavonoids can regulate epigenetic modification, transcription, and change microRNA (miRNA) expression of GBM through lncRNA at the gene level. It also found that flavonoids can induce apoptosis and autophagy of GBM cells by regulating lncRNA. Moreover, it can improve the metabolic abnormalities of GBM, interfere with the tumor microenvironment and related signaling pathways, and inhibit the angiogenesis of GBM cells. Eventually, flavonoids can block the tumor initiation, growth, proliferation, differentiation, invasion, and metastasis. In this review, we highlight the role of lncRNA in GBM cancer progression and the influence of flavonoids on lncRNA regulation. And emphasize their expected role in the prevention and treatment of GBM.