ScopeThis study aims to investigate the effect and mechanism of Urolithin A (UA) on neuronal stress damage on cognitive impairment in type 2 diabetes mellitus (T2DM) mouse model induced by high‐fat diet (HFD) and streptozotocin (STZ).Methods and resultsT2DM mice fed with UA display an attenuated cognitive impairment along with suppressed endoplasmic reticulum (ER) stress and Tau hyperphosphorylation in brain. Similar restraint effect of UA on Tau hyperphosphorylation and ER stress is also observed in high glucose‐treated primary hippocampal neurons. Moreover, UA ameliorates oxidative stress, ER stress, aberrant energy metabolism, and apoptosis in 2,3‐dimethoxy‐1,4‐naphthoquinone (DMNQ) induced HT22 cells. Atp2a3 is identified as a potential target gene of UA which is closely related to intracellular calcium homeostasis, ER stress, and apoptosis, so that UA significantly down‐regulated Atp2a3 expression in DMNQ‐induced cells. Furthermore, the protection effect of UA against ER stress and apoptosis is abolished by Atp2a3 over‐expression in HT22 cells. Taken together, these data suggest that UA performs anti‐stress effect by suppressing the expression of Atp2a3 in damaged neuronal cells and thus attenuates diabetes‐associated cognitive impairment in T2DM mice.ConclusionThe study implies UA as a potential novel pharmaceutic target for neurodegeneration and stress damage through regulating the expression of Atp2a3.