Alzheimer’s disease (AD) is a major neurodegenerative disorder, characterized by amyloid‑beta deposition and tau aggregation. Recently, Tau‑targeted approaches have gained attention because amyloid‑based therapies have shown limited success in clinical trials. Accumulating evidence indicates that tau pathology is more closely associated with AD pathology. This study aimed to examine the potential therapeutic effects of Azelnidipine, the L-type calcium channel blocker, in mouse model. Azelnidipine is FDA-approved antihypertensive drug that has been reported to inhibit MEK/ERK signaling, which may help reduce tau pathology. In addition, by limiting calcium overload, Azelnidipine may further contribute to reduced tau levels and cognitive decline. To evaluate these effects, PS19 transgenic mice were orally treated Azelnidipine for one month. Cognitive function was evaluated using the Morris water maze and passive avoidance tests, and brain tissues were collected for molecular analysis. Azelnidipine treatment markedly reduced phosphorylated tau levels in PS19 mouse brains and improved memory retention in behavioral tests. Although MEK/ERK sigaling was not significantly altered, phosphorylated PKA expression was notably decreased. These findings suggest that Azelnidipine ameliorates tau pathology and cognitive impairment in an AD mouse model. Given its established safety as an antihypertensive, it may be a promising therapeutic candidate for Alzheimer’s disease.