The invention discloses a high-activity long-acting blood-glucose-reducing fusion protein, which is formed by connecting a high-activity exenatide mutant to an Fc fragment in optimized mutational human immunoglobulin IgG1 through a connecting peptide or directly. The Fc fragment in the optimized mutational human immunoglobulin IgG1 includes a hinge region of the optimized mutational human IgG1 and constant regions CH2 and CH3 of the human IgG1. The fusion protein not only has long-acting blood-glucose-reducing effect but also can be solubly expressed in E.coli, wherein an expression product can be directly separated and purified from a bacterial cell disruption supernatant. The fusion protein greatly simplifies production process, is increased in product yield and is reduced in production cost.