Objective To investigate the effect of modified Dioscorea opposita Thunb. Pill on the expression of glycogen synthase kinase-3β (GSK-3β) and cyclin D1 in the hippocampus of rats with vascular dementia (VD) and its mechanism of action in the prevention and treatment of VD. Methods A total of 40 specific pathogen-free male Wistar rats were divided into normal group, model group, Western medicine group, and traditional Chinese medicine (TCM) group, with 10 rats in each group. Modified ligation of both common carotid arteries was performed to establish a rat model of VD. The rats in the TCM group and the Western medicine group were given modified Dioscorea opposita Thunb. Pill and nimodipine, respectively, by gavage, and those in the normal group and the model group were given normal saline by gavage. The course of treatment was 6 consecutive weeks for all groups. Histomorphological changes of neural cells in the hippocampus of rats were observed under a light microscope, Western blot was used to measure the expression of GSK-3β in the hippocampus, and immunofluorescence assay was used to measure the expression of cyclin D1 in the hippocampus. Results Compared with the model group, the TCM group and the Western medicine group had significant relief of lesions in neural cells in the hippocampus of VD rats under the light microscope. The Western blot and immunofluorescence assay showed that compared with the model group, the TCM group and the Western medicine group had a significant reduction in the level of GSK-3β (P<0.05) and a significant increase in the expression of cyclin D1 in the hippocampus (P<0.05), and there were no significant differences in the expression of GSK-3β and cyclin D1 between the TCM group and the Western medicine group (P>0.05). Conclusion Modified Dioscorea opposita Thunb. Pill can protect neural cells in the hippocampus of VD rats by activating the Akt pathway to inhibit the expression of GSK-3β and upregulate the expression of cyclin D1.