Systemic lupus erythematosus (SLE) is a systemic autoimmune disease resulting in loss of self-tolerance with multiple organs, such as the kidney, skin, joints, and the central nervous system (CNS), being targeted. Numerous immunosuppressant therapies are currently being used for the treatment of SLE, but their clinical utility is somewhat variable because of the clinical heterogeneity. Melanocortins are a family of peptides derived from the common precursor protein pro-opiomelanocortin. These multifunctional peptides activate five subtypes of melanocortin receptors expressed on immune, skin, muscle, bone, and kidney cells and cells within the CNS. Melanocortin peptides have demonstrated a variety of biologic actions including immunomodulation, melanogenesis, and renoprotection. This review aims to introduce the melanocortin system and explore the mechanisms by which they may be beneficial in diseases such as SLE.