Thrombospondin-1 (THBS1) is a multifunctional extracellular matrix protein that interacts with cell surface receptors such as CD36, CD47 and integrins, as well as proteins such as angiogenic factors and transforming growth factor (TGF)-β. THBS1 affects the development of skin diseases at the molecular level by regulating processes such as angiogenesis, fibrosis, inflammation and tumor growth. This review systematically investigates the signaling mechanisms of THBS1 in the skin. It emphasizes their influence on wound healing, tissue regeneration, inflammatory reactions, fibrosis and the development of skin tumors. THBS1 thus combines basic research with clinical dermatology. By investigating these aspects, the roles of THBS1 in difficult-to-treat skin diseases are clarified. It has potential as a target for therapy.