Abstract: This study was designed to investigate the therapeutic effect of novel compound Z-9-octadecenyl-2-propanesulfonamide (N15) on diabetes-associated cognitive decline (DACD). Type 2 diabetes (T2DM) mice models were established with multiple injection of low doses of streptozotocin (STZ) in mice on high fat diet (HFD). Vehicle and different concentrations of N15 (50 and 100 mg·kg^-1·d^-1) were administrated orally for 6 weeks. The step-down test, dark avoidance task and Morris water maze were conducted at the 6^th week. The level of glucose and lactic acid in hippocampus were determined and mRNA of growth associated protein-43 (GAP-43), synaptophysin (SYN), brain derived neurotrophic factor (BDNF) and neurotrophins-3 (NT-3) in hippocampus were analyzed by real time PCR. The beneficial effects of N15 on learning and memory were found in the test of step-down, dark avoidance and Morris water maze. N15 reduced the level of glucose and lactic acid in hippocampus of HFD+STZ-induced diabetic encephalopathy model mice. Additionally, the mRNA expression of GAP-43, SYN, BDNF and NT-3 in hippocampus of HFD+STZ-induced diabetic encephalopathy mice were significantly increased by N15 (P<0.01). These results suggest that the novel compound N15 can ameliorate diabetes-associated cognitive decline and the potential mechanism may be associated with the expressions of increased synaptic-related factors and neurotrophic factor in the hippocampus of diabetesassociated cognitive decline in mice.