An injectable thermogel composed of poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was evaluated as the matrix of a long-acting drug delivery system of exenatide (EXT), an antidiabetic peptide. The optimal gel formulation containing 2 mg/mL EXT and three pharmaceutical excipients (1.25 wt % zinc acetate, 5 wt % PEG200, and 5 wt % sucrose) was injected subcutaneously, and its pharmacokinetics was investigated. Both in vitro and in vivo release profiles exhibited a sustained release of EXT over 1 week. After a subcutaneous injection of the EXT formulation into db/db mice, the blood glucose level was maintained in a normal range up to 7 days and meanwhile the growth of body weight was suppressed. The in vivo results were consistent with the in vitro EXT-release profile. Moreover, twice injections of the gel formulation resulted in the higher blood insulin level and lower plasma concentration of glycosylated hemoglobin compared with twice-daily injections of an EXT solution for 18 days. Histological observations manifested the protection of islet due to administration of the gel formulation. Therefore, the PLGA-PEG-PLGA thermogel provided an excellent candidate for a once-weekly delivery system of EXT, and the optimal EXT formulation not only afforded therapeutic efficacy but also improved patient compliance.