G protein-coupled receptors (GPCRs) are a large family of transmembrane proteins that are expressed in many organs and serve as important drug targets. A new subgroup, namely orphan GPCRs, comprising many of these receptors has been discovered. These receptors exhibit diverse physiological functions and have been considered in many neurological disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis (MS). GPR17, GPR30, GPR37, GPR40, GPR50, GPR54, GPR56, GPR65, GPR68, GPR75, GPR84, GPR97, GPR109, GPR124, and GPR126 are orphan GPCRs that have been reported with considerable effects in the prevention and/or treatment of MS in preclinical studies. In the present article, we reviewed the most recent findings regarding the role of orphan GPCRs in the treatment of MS.