Objective To explore the effects of Shenzhiling oral liquid ( SZL) on neuronal nitric oxide synthase (nNOS) and carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) interaction, and determine which downstream extracellular signal-regulated kinase ( ERK) / cAMP-response element binding protein ( CREB) signaling pathway regulates the learning and memory ability in a mouse model of sporadic Alzheimer’ s disease ( SAD). Methods Twelve of 72 C57BL/ 6J male mice were randomly selected as the control group. The remaining 60 mice had streptozotocin injected into the bilateral ventricles on the first and third days to create a model of SAD; the streptozotocin was replaced with an equal volume of artificial cerebrospinal fluid in the control group. The 60 SAD mice were randomly divided into the model group, donepezil group, high-dose SZL(SZL-H), medium-dose SZL(SZL-M) and low-dose SZL(SZL-L) groups. Each intervention group was gavaged with the corresponding drug for 3 months, whereas the control group and model group were gavaged with the same volume of 0. 5% sodium carboxymethyl cellulose. The Morris water maze was used to test the escape latency and number of times each mouse crossed the platform after being removed from the platform. The number of synapses in the hippocampal CA1 region in each group was observed by transmission electron microscopy. The interaction between nNOS and CAPON in the hippocampus was detected by co-immunoprecipitation. The distribution and presence of ERK and CREB cells in the hippocampal CA1 region were observed by immunohistochemical staining. Western blot analysis was used to detect the expressions of ERK, p-ERK, CREB and p-CREB in hippocampal tissue. Results Compared with the control group, the model group had significantly increased escape latency ( P< 0.01), decreased frequency of platform crossing (P< 0. 01), decreased number of synapses in the hippocampal CA1 region ( P< 0. 01), increased interaction between nNOS and CAPON (P<0.01), similar expression of ERK (P>0. 05), decreased expressions of p-ERK, CREB and p-CREB ( P< 0.01), and decreased concentrations of p-ERK/ ERK and p-CREB/ CREB ( P< 0. 01). Compared with the model group, the donepezil and SZL intervention groups had significantly decreased escape latency (P<0.05 or P<0.01), increased frequency of platform crossing (P<0.01), increased numbers of synapses in the hippocampal CA1 region (P<0. 01), decreased interaction between nNOS and CAPON (P<0.05 or P<0.01), similar expression of ERK ( P> 0.05), increased expressions of p-ERK, CREB and p-CREB ( P<0. 05 or P< 0.01), and increased concentrations of p-ERK/ ERK and p-CREB/ CREB (P<0.01). Conclusions SZL improves the learning and memory ability of mice with SAD by decreasing the interaction between nNOS and CAPON and increasing the expression of ERK/ CREB pathway-related proteins and the number of synapses.