Objective In this study, we aimed to investigate the effects of different doses of n-butylphthalide (NBP) on cognitive function in db / db mice, the expression of synaptophysin (SYN) and post-synaptic density-95 (PSD- 95) proteins in the hippocampus, as well as mitochondrial structure in the hippocampus. Methods A total of 20 db / db mice were randomly divided into four groups: model group, and low, medium and high-dose treatment groups (five mice in each group). In addition, five normal db / m mice from the same litter were used as the control group. At the age of 6 weeks, db / db mice in the low, medium and high-dose groups were intraperitoneally injected with NBP at a concentration of 20, 40 and 60 mg / kg, respectively, while the control group and the model group were given the same volume of normal saline. Injections were given once a day for 6 weeks. Body weight and fasting blood glucose level were monitored weekly. Morris water maze was used to assess spatial learning and memory abilities. Western blot was used to detect the expression of SYN and PSD-95 in the hippocampus, and the structure of hippocampal mitochondria was observed by electron microscopy. Results Compared with the model group, there was no significant difference in body weight or blood glucose in any treatment group. However, during the water maze exploration period, escape latency was reduced (P< 0. 05), the number of platform crossings was increased (P< 0. 01), protein expression levels of SYN and PSD-95 in the hippocampus were increased (P< 0. 05), and there was a positive relationship between cognitive improvement and protein expression. Under the electron microscope, mitochondrial structure in the control group was normal, the ridge structure was clear and tightly arranged, and the membrane structure was intact. In the model group, mitochondria were damaged, and cristae were sparse, fused and vacuolated. In the treatment groups, most of the mitochondria in the hippocampus were intact, while cristae structure was slightly perturbed, and membrane structure was relatively intact. Conclusions NBP alleviates cognitive dysfunction in db / db mice by regulating the expression of the hippocampal synaptic proteins SYN and PSD-95, and by improving mitochondrial structure. The therapeutic effect in the high dose group was better than that in the low and medium-dose groups.