Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer syndrome characterized by an increased risk of early-onset and multiple tumors across various organ systems, predominantly linked to germline TP53 mutations. While commonly associated neoplasms include sarcomas, breast cancer, and adrenocortical carcinoma, the occurrence of high-grade gliomas (HGG), including glioblastoma multiforme (GBM), in LFS patients is less documented and typically presents at a younger age relative to sporadic cases. A systematic review following PRISMA guidelines was conducted, focusing on clinical studies and case reports that explore the association between HGG and LFS. A comprehensive PubMed search was used to capture relevant studies. The inclusion criteria focused on patients with a confirmed diagnosis of LFS and histopathologically verified HGG. A total of 248 articles were initially identified, with 8 studies meeting the final inclusion criteria after independent review and consensus. Overall, 8 studied reported on patients with either WHO grade 3 or 4 gliomas in the setting of LFS. In total these studies represent 12 patients, with 8 (66%) WHO grade 4, and 4 (33%) WHO grade 3. 9 (75%) patients underwent maximal safe resection, 5 (42%) underwent concurrent TMZ and EBRT. 9 (75%) patients underwent external beam radiation therapy (EBRT), 1 (8%) underwent intensity modulated radiation therapy (IMRT), and 1 (8%) underwent adjuvant treatment with tumor treating fields (TTF) therapy. Overall chemotherapy utilization was 75% with 9 patients receiving some form of chemotherapy. The median time to recurrence following initial treatment was 7 months (IQR: 2.00-7.00). Time to progression was variable, ranging from 5.1 months to 7 years. 64% of patients succumbed to their disease with a median OS of 17 months across studies. LFS associated HGGs are a genetically heterogenous entity. Detailed study of outcomes reported in the literature with respect to these genetics will develop further insight into therapeutic response and prognostication.