Red blood cells (RBCs) or erythrocytes are highly vulnerable to oxidative stress due to their absence of nuclei and mitochondria, presence of iron containing heme and high amounts of fatty acids in their uniquely constructed lipid bilayer membrane. The principal function of RBCs is to carry oxygen to tissues. Thus, RBCs have to pass through the micro-capillaries in which it requires these cells exhibits high structural deformability and great elasticity. The intact cytoskeletal architecture and proper membrane fluidity of RBCs are crucial for their deformability. Many factors can jeopardize the structural and functional harmony of RBCs. One of them is ROS which causes RBC oxidative injuries manifested by hemolytic anaemia such as occurring in β-thalassemia. Melatonin, as a potent free radical scavenger and antioxidant, can effectively protect against RBC oxidative injuries. In addition, melatonin chelates the free iron and upregulates gene expression of antioxidant enzymes of RBCs. Melatonin is synthesized and highly accumulated in RBCs to exhibit the on-site protection. All of these indicate that melatonin is a best molecule to preserve the structural and functional intactness of RBCs. This review tries to update the current development in the field and suggests the potential utility of melatonin on the RBC related disorders.