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Objective: Fibroblast growth factor 21 (FGF-21) is an endocrine factor playing important role in energy metabolic pathways and might be a potential therapeutic target for metabolic disorders such as type 2 diabetes (T2D) and NASH. However, Wild type FGF-21’s clinical application is hindered due to its limited bio-activity. To enhance the medicinal properties, this study mutated FGF-21 to improve its bio-activity. And based on potential synergistic effect of GLP-1 and FGF-21, a FGF-21/GLP-1 fusion protein was constructed to develop a potential T2D/NASH effective drug. Methods: FGF-21-Fc was mutated to enhance its receptor interaction and stability. FGF-21 mutants’ blood glucose reduction capability were compared on db/db mice. Moreover, by constructing a dual agonist from FGF-21 and GLP-1, the bio-activity was further enhanced. Using HFD ob/ob mice, the dual agonist was evaluated by measuring multiple indicators such as blood glucose level, body weight, liver function, and the NAS score. Results: Results from db/db mice (n=9, single SC injection, 40nM/kg) show that the mutated FGF-21-Fc possesses significantly stronger blood glucose lowering effect than the wild type (P<0.01). Results from HFD ob/ob mice (n=8, SC injection, BIW, 4 weeks) show that the dual agonist reduces the blood glucose level by 60% or more (P <0.001), reduces ALT levels by more than 70%, and reduces NAS scores by more than 3 points. The dual agonist is more effective than dulaglutide on T2D and NASH (P<0.001). Conclusions: According to this study, FGF-21 and GLP-1 can synergistically enhance the metabolic regulation through multiple mechanisms. The mutated dual agonist possesses optimized bio-activity and shows significant improvements for T2D and NASH. It is a very promising drug for both T2D and NASH treatment. Disclosure L. Guo: None. Q. Pan: None. C. Chen: None. S. Lin: None. Y. Li: None. X. Li: None. X. Chen: None. L. Liu: None. W. Li: None. X. Tang: None.