Thyroid hormone is essential for metabolism, nerve excitability and physical development. Congenital hypothyroidism leads to dysfunction of neuronal migration for thyroid hormone deficiency, and even delays psychomotor formation and development in serious congenital hypothyroidism. Congenital hypothyroidism presents a higher rate of incidence (1/2,500) in infants and is the most common causes of mental retardation. Fibroblast growth factors-21 (FGF-21) is an endogenous metabolism regulate factor that increases energy consumption, reduces blood lipid, triglyceride, low density lipoprotein levels, enhances the capacity of fat cells to absorb glucose and suppresses glucagon secretion. The purpose of this study was to investigate the changes of FGF-21 level and the efficacy of FGF-21 for mice with congenital hypothyroidism. The therapeutic efficacy of FGF-21 was conducted in an intravenous injection manner in a congenital hypothyroidism mouse model. The therapeutic outcomes of FGF-21 for mice with congenital hypothyroidism were assessed by animals’ behaviours. Our results found that FGF-21 levels were significantly lower both in serum and thyroid in congenital hypothyroidism mouse model than that in healthy subjects (**P<0.01). We observed that T4 and TSH were up-regulated in thyroid after FGF-21 treatment. The serum levels of FGF-21 and FGF-21 concentration in thyroid were higher than those in control groups (**P<0.01) after treatment with FGF-21. The serum levels of FGF-21 in thyroid was and positively related with thyroid stimulating hormone (TSH) and thyroxine (r=0.832, **P<0.01; r=0.381, **P<0.01; r=0.733, respectively). Multiple linear regression analysis showed that in hypothyroidism, FGF-21 was decreased and independent factors influencing serum TSH levels. Taken together, we provided evidence for protein diagnosis and potential efficacy of FGF-21 for congenital hypothyroidism.