Objective To determine the effects of TDZD-8, inhibiter of glycogen synthase kidnase 3β(GSK-3β), on the expression of Tau protein hyperphosphorylation, pathological change in neuron and incidence of DNS after CO poisoning. Methods The rat CO poisoning model was established with introducing CO into abdominal cavity. The survival rats were randomly divided into two groups: CO poisoning group(Mod group) and low-dose group(0.5mg/kg)(TL group),middle-dose group(1.0mg/kg) (TM group) and high-dose group(1.5mg/kg) (TH group)of TDZD-8.all rats received hyperbaric oxygen therapy for six days. Morris water maze was adopted 15 days after CO poisoning to identify DNS happening. The pathological change was observed by hematoxylin and eosin staining. The expression of hyperphosphorylated Tau protein was determined by immunohistochemical staining. Results After CO poisoning ,compared with Mod group, the cognitive function, brain tissue pathological damage,incidence of DNS and expression of Tau protein hyperphosphorylation of TDZD-8 intervention groups were improved,especially in TM group. There were more P-tau(Ser199) positive cells in DNS rats than those in non- DNS rats. conclusion Tau protein hyperphosphorylation may be involved in the pathological process of DNS after CO poisoning. TDZD-8 had a protective effect to cerebral injury of DNS rats after CO poisoning.