The present invention belongs to the technical field of biological pharmacy, and particularly relates to a long-acting HM-3 fusion protein molecule and an application thereof. In the present invention, on the basis of the sequence of HM-3 molecule, an active polypeptide HM-3 and derivatives thereof are linked to a human Fc (IgG) fragment or a fragment of an Fc (IgG) mutant directly or by a linker peptide (Linker), thus forming a novel molecular entity. The general formula of the molecular entity is (HM-3)n-Linker-Fc(IgG), Fc(IgG)-Linker-(HM-3)n, or (HM-3)n-Linker-Fc(IgG)-Linker-(HM-3)n. The fusion protein effectively prolongs the half-life of HM-3, is low in cost and overcomes the major problem of druggability of small peptides. Therefore, the fusion protein of the present invention may serve as a potential drug for the treatment of autoimmune diseases, neovascular diseases, osteoarthritis and the like.