To explore the effect and mechanism of Tiepi Fengdou Granules(TPFD) for replenishing qi and nourishing yin by establishing a mouse model of qi and yin deficiency.Methods:A total of 60 male ICR mice were randomly divided into blank group，model group，Yupingfeng Granules group，and TPFD high-，medium-and low-dose groups，with 10 in each group，and were administered for 30 consecutive days.In the experiment，a mouse model of qi and yin deficiency was established by providing the mice time restricted eating on odd days and weight-bearing exhaustive swimming on even days in combination with levothyroxine sodium tablets(ig).The general state of the mice was dynamically observed，and the body weight，organ index，limb grip strength and exhaustive swimming time were determined.The related indexes of cyclic adenosine monophosphate(cAMP)，cyclic guanosine monophosphate(cGMP)，interleukin-6(IL-6)，complement component 3(C3)，cortisol(CORT)，adrenocorticotropic hormone(ACTH)，corticotropin releasing hormone(CRH)，triiodothyronine(T3)，thyroxine(T4)，thyroid-stimulating hormone(TSH)，estradiol(E2) and testosterone(T) in serum were detected by enzyme linked immunosorbent assay(ELISA).The mRNA expressions of protein kinase A(PKA) and cyclic-AMP response element binding protein(CREB) in hypothalamus were detected by real-time quantitative polymerase chain reaction(Real-time PCR).Results:Compared with the model group，the administration groups had improved general state.On the 30th day of the experiment，the body weight in both TPFD high-and medium-dose groups was increased(P<0.01).High-dose TPFD increased the thymus index，spleen index and limb grip strength of the mice，prolonged the exhaustive swimming time(P<0.05，P<0.01)，reduced the serum levels of cAMP，cAMP/cGMP，T3，E2，E2/T and IL-6(P<0.05，P<0.01) and the mRNA expression of PKA in hypothalamus(P<0.01)，and increased the serum levels of T and C3(P<0.01).TPFD up-regulated the serum level of TSH at a medium dose(P<0.01) while down-regulated the mRNA expression of CREB in hypothalamus at a low dose(P<0.05).Conclusion:TPFD improves the general state of mice with qi and yin deficiency.It up-regulates the PKA/CREB signaling pathway by regulating the cyclic nucleotide-endocrine system-immune system network，to exert the effect of replenishing qi and nourishing yin.