Significance Glioblastomas and neuroblastomas are aggressive cancer types with poor prognosis. Identification of druggable factors that inhibit these tumors will contribute to new therapies. Our data show that nuclear receptor NR5A2 suppresses the growth of glioblastomas and neuroblastomas. This function is facilitated by the ability of NR5A2 to induce critical cell cycle inhibitors including p21, p27, and Prox1. Two small molecule agonists of NR5A2, dilauroyl phosphatidylcholine, and diundecanoyl phosphatidylcholine can mimic its antitumor effect. Our results identify NR5A2 as a potential drug target in nervous system–related cancers.