Metabolic regulation in the nervous system plays a pivotal role in orchestrating neuronal function and maintaining cellular homeostasis. Utilizing our RNAseq data from gain- and loss-of-function studies of embryonic neural tissue and neuronal cells, we demonstrate that the nuclear receptor NR5A2 regulates hypoxia response, glycolysis, and fatty acid metabolism. Consistently, we have previously shown that NR5A2 inhibits the proliferation and growth of glioblastoma cells and tumors, respectively. Here, we elucidate a novel mechanism whereby NR5A2 functions as a potent suppressor of HIF-1α (Hypoxia-Inducible Factor 1-alpha), independent of prolyl hydroxylase (PHD)-mediated inhibition. This repression of HIF-1α by NR5A2 leads to the downstream inhibition of the genes that are direct targets of HIF-1α and code for proteins that are crucial players in metabolic pathways such as glycolysis, fatty acid and glutathione metabolism, thereby reshaping the metabolic landscape within neural and glioblastoma cells. This mechanism could also contribute to the antiproliferative, antigliogenic, and anti-tumorigenic properties of NR5A2 in the context of GBM and neural/stem progenitor cells. Notably, pharmacological activation of NR5A2 using DLPC (Dilauroylphosphatidylcholine), a well-established agonist, mirrors the anti-tumorigenic effects observed with NR5A2 overexpression. These data highlight DLPC or other agonistsof NR5A2 as a promising therapeutic molecule for glioblastoma multiforme, a very aggressive malignancy of the central nervous system. Overall, our study uncovers a link between NR5A2-mediated metabolic regulation, neuronal development, and inhibition of glioblastoma tumor progression. These observations suggest that NR5A2 and its agonists could be used as potential therapeutic targets for nervous system malignancies and/or other nervous system-related diseases.