Mitochondrial dysfunction has been detected in the brains of patients with autism spectrum disorders (ASD) with unclear mechanisms. We herein identify that G protein-coupled receptor 50 (GPR50), which harbors two variations in male ASD patients at Δ502-505 and T532A, is required in mitophagy. GPR50, which does not distribute endogenously in the mitochondrion, is recruited to the damaged mitochondrion, where it marks the mitochondrial portion and recruits the assembling autophagosomes, eventually facilitating itself with the mitochondrial fragments to the autophagosomes. The above process is ascribed to a direct binding of GPR50 to LC3. In this way, GPR50 is required in CCCP-induced mitophagy. Defective GPR50-mediated mitophagy results in an abnormal conversion of mitochondrial metabolism to glycolysis from oxidative phosphorylation (OXPHOS), which leads to insufficient ATP production and excessive ROS generation. Both Δ502-505 and T532A mutations attenuate GPR50-mediated mitophagy. Deficiency of GPR50 results in impaired neuronal development and autism-like behaviors in mice, which are rescued by the administration of mitoQ at the earlier embryonic stage. The present study identifies GPR50 as a novel mitophagy regulator and provides evidence that defective mitophagy contributes to the pathogenesis of ASD.