BACKGROUND: Cognitive decline in the normal aging process is one of the most common and prominent problems. Delaying and alleviating cognitive impairment is an important strategy of anti-aging. This study is to aim at investigating the effects of Yinxing-Mihuan-Oral-Liquid(GMOL) on the CREB/BDNF signaling in the normal aging process.METHODS: SD rats were randomly divided into GMOL group and control group. The Morris water maze (MWM) was introduced for behavioral test. Immunohistochemistry and immunofluorescence were used for cAMP response element binding protein 1(CREB1), p-CREB(Ser133), brain-derived neurotrophic factor(BDNF), synaptophysin(SYP) and glial fibrillary acidic protein(GFAP). Western blot was conducted for investigating the levels of CREB1 and p-CREB(Ser133), BDNF, SYP, GFAP and interleukin 6(IL-6). RESULTS: Our data showed that compared with the control group, GMOL group had higher expression of memory-related proteins, decreased inflammatory factors, and enhanced spatial learning and memory ability.CONCLUSION: The study results show that GMOL ameliorates cognitive impairment of the normal aged SD rats via enhancing the expression of memory biomarkers and inhibiting inflammatory process. The potential neuroprotective role of GMOL in the process of aging may be related to mitigating cognitive decline via activating CREB/BDNF signaling and inhibiting inflammatory process.