Exenatide, an analogue of glucagons-like peptide 1 (GLP-1), consists of 39 amino-acid residues and adjusts blood glucose level through bidirectional hormone-targeted regulation. However, there are still many challenges about its synthetic methods. Herein, we split Exenatide into six fully protected peptide fragments and each fragment was synthesized by the solid-phase or liquid-phase method, respectively. After two-step cleavages and purifications, the final products 0.98 g (yield: 33.8%, Purity﹥98%) is obtained. The Fmoc- protective group attached to the Exenatide after the first step cleavage can enhance the separation of target and impurity efficiently in purification step. The results show that, with the advantages of both solid-phase and liquid-phase method, is an short-cycled, more convenient method and the yield is higher.