Aim: In this study, OXYS rats of three ages (1, 3, and 6 months), a proven model of Alzheimer’s disease (AD), at various stages of disease progression were used to thoroughly study the effects of amisulpride on behavior and tau protein phosphorylation. Background: With the growing number of patients with AD, the problem of finding a cure is very acute. Neurodegeneration in AD has various causes, one of which is hyperphosphorylation of tau protein. Objective: This study aimed to investigate whether amisulpride would affect pathological tau phosphorylation in AD. Methods: We assessed the influence of chronic administration of amisulpride (3 weeks, 3 mg/kg per day, intraperitoneally)-a 5-HT7 receptor inverse agonist-on behavior and tau hyperphosphorylation in OXYS rats (at ages of 1, 3, and 6 months). Results: Chronic administration of amisulpride dramatically decreased tau phosphorylation in the frontal cortex and hippocampus of 3-month-old OXYS rats. Additionally, in 1- and 3-month-old rats’ hippocampi, amisulpride diminished the mRNA level of the Cdk5 gene encoding one of the main tau kinases involved in the 5-HT7 receptor-induced effect on tau phosphorylation. Conclusion: Thus, we propose amisulpride to have therapeutic potential against AD and that it can be the most effective in the early stages of the disease. We found that chronic administration of amisulpride could reduce pathological tau hyperphosphorylation while reducing anxiety.