Fibroblast growth factor-21 (FGF-21) is a new member of the FGF family and potential drug candidate for the treatment of type 2 diabetes mellitus. However, FGF-21 protein has short half-life in vivo, which severely affects its clinical application. In the present study, PEGylated FGF-21 was prepared by modifying the N-terminus of hFGF-21 with 20 kDa mPEG-ALD. The long-acting hypoglycemic effect of PEGylated FGF-21 and liraglutide was compared on type 2 diabetic db/db mice. The pharmacological efficacy of the compounds was evaluated by blood glucose levels, body weight, glycosylated hemoglobin levels, insulin levels, oral glucose tolerance test, lipid levels, and liver function parameters. We noticed that both PEGylated FGF-21 and liraglutide could significantly decrease plasma glucose in db/db mice. However, comparing to liraglutide treatments, PEGylated FGF-21 therapy resulted in more significant effect in lowering blood glucose levels and glycosylated hemoglobin levels, alleviating insulin resistance, improving lipid profile, liver function, and glucose control of the experimental mice. Our results suggest that PEGylated FGF-21 appears more beneficial anti-diabetic effect in type 2 diabetic mice than liraglutide, which holds significant promise as an ideal candidate for the treatment of type 2 diabetic patients.