Background: Alzheimer disease (AD) is the most common age‑, dependent dementia. The complex natural accumulation of amyloid beta (Aβ, ) precursor protein in hippocampus neurons is regarded as the earliest pathological feature of AD, although there are cholinergic assumptions and effective inflammation in AD. In this animal experimental study, we evaluated the preventive effect of hyoscyamoside (Hyo) and donepezil (Dz) on plaque formation and improvement of neurogenic inflammation in AD rats. Methods: Dz was prepared and Hyo (steroidal saponin) was isolated from Hyoscymus niger. Then, Wistar rats divided into five groups including negative and positive controls, AD, Dz, and Hyo treatment groups based on the drug exposure and their behavioral alternation was examined using Morris water maze (MWM) test. Bielschowsky staining was used to detect the nerve fibers. Serum levels of interleukin (IL)‑, 4 and IL‑, 6 were evaluated by ELISA. The RNA expression of cyclin‑, dependent kinase CDK11-P58 in peripheral blood lymphocytes was performed using quantitative PCR. Results: The MWM test showed significant changes in time the models spent to find the hidden platform. The Hyo treatment group showed a notable speed change (P < 0. 01). The histopathological analysis of the hippocampal tissue revealed the inhibition of Aβ,formation in the treatment groups. The treatment groups had a significant decline in the serum level of IL‑, 6, and the IL‑, 4 serum level was increased in the Hyo and Dz treated groups. The expression levels of CDK11-P58 was significantly decreased in the treatment groups. Conclusions: In sum, the therapeutic effects of Hyo is comparable with that of Dz in AD rats by suppressing neuroinflammation. Thus, these compounds could be considered as a preventive agent in the AD therapy.