The melanocortin-4 receptor (MC4R) plays an important role in the regulation of food intake and energy expenditure. Melanocortin-2 receptor accessory protein 2 (MRAP2) modulates trafficking, ligand binding, and signaling of MC4R. The Northern snakehead () is an economically important freshwater fish native to East Asia. To explore potential interaction between snakehead MC4R and MRAP2, herein we cloned snakehead and . The snakehead consisted of a 984 bp open reading frame encoding a protein of 327 amino acids, while snakehead contained a 693 bp open reading frame encoding a protein of 230 amino acids. Synteny analysis indicated that was highly conserved with similar gene arrangement, while contained two isoforms in teleost with different gene orders. Snakehead was primarily expressed in the brain, whereas was expressed in the brain and intestine. Snakehead and expression was modulated by fasting and refeeding. Further pharmacological experiments showed that the cloned snakehead MC4R was functional, capable of binding to peptide agonists and increasing intracellular cAMP production in a dose-dependent manner. Snakehead MC4R exhibited high constitutive activity. MRAP2 significantly decreased basal and agonist-stimulated cAMP signaling. These findings suggest that snakehead MC4R might be involved in energy balance regulation by interacting with MRAP2. Further studies are needed to elucidate MC4R in regulating diverse physiological processes in snakehead.