The present invention belongs to the technical field of biological pharmacy, and more in particular, relates to a long-acting HM-3 fusion protein molecule and the use thereof. In the present invention, based on the sequence of the HM-3 molecule, a completely new molecular entity is formed by linking the active polypeptide HM-3 and derivatives thereof to a human Fc (IgG) fragment or an Fc (IgG) mutant fragment via a linker peptide (Linker) or directly, and the new molecular entity has the general formula of (HM-3) n-Linker-Fc(IgG), Fc(IgG)-Linker-(HM-3) n or (HM-3) n-Linker-Fc(IgG)-Linker-(HM-3)n. The present invention effectively prolongs the half-life of HM-3, is low in cost, and also overcomes the key problem of druggability of small peptides. The fusion protein can be used as a drug with great potential for treating autoimmune diseases, neovascular diseases and osteoarthritis, etc.