This study aimed to investigate the effect of Angelica sinensis polysaccharides (ASP) on Alzheimer’s disease (AD) and its underlying mechanisms. In our study, we build the AD model by injecting Aβ25–35. Morris water maze (MWM) was applied to investigate learning and memory. Moreover, neurotransmitters, free radical, and inflammatory factors were also measured. Pathological change and neuronal death in hippocampus CA1, CA3, and DG region were detected by HE staining and Nissl staining. The neuronal apoptosis was detected by TUNEL. The expressions of caspase-3, Bcl-2 and Bax were measured by immunohistochemistry and Western blot. The expressions of BDNF, TrkB, p-Akt, Akt, p-CREB, and CREB were measured by Western blot. Our results showed that ASP could ameliorate spatial learning and memory deficiency in AD rats. ASP decreased AchE level and increased the levels of Ach and chAT in AD rats. ASP could increase the activity of SOD and CAT, decrease MDA activity, and inhibit the expression levels of inflammatory factors and neurons apoptosis in AD rats. Pathological change of hippocampus CA1, CA3, and DG region was ameliorated by ASP. In addition, the effects of ASP were reversed by K252a (TrkB inhibitor). Our study demonstrated that ASP could ameliorate memory impairment in AD rat through activating BDNF/TrkB/CREB pathway. Impact statement The present study demonstrated that ASP could ameliorate memory impairment through regulation of the balance of neurotransmitters, free radical metabolism, inflammation, and neurons apoptosis. Moreover, the mechanism of ASP on memory impairment may be related to BDNF/TrkB/CREB pathway in AD. Our research provides an innovatively regulatory mechanism about the ASP in AD rat and points a new way to the treatment of AD.