Although doxorubicin (Dox) is an effective chemotherapy medication used extensively in the treatment of breast cancer, it frequently causes debilitating neurological deficits known as chemobrain. Donepezil (DPZ), an acetylcholinesterase inhibitor, provides therapeutic benefits in various neuropathological conditions. However, comprehensive mechanistic insights regarding the neuroprotection of DPZ on cognition and brain pathologies in a Dox-induced chemobrain model remain obscure. Here, we demonstrated that Dox-treated rats manifested conspicuous cognitive deficits and developed chemobrain pathologies. Intervention with DPZ co-treatment completely restored cognitive function by attenuating these pathological conditions induced by DOX. We also confirmed that DPZ treatment does not affect the anti-cancer efficacy of Dox in breast cancer cells. Together, our findings suggest that DPZ treatment confers potential neuroprotection against Dox-induced chemobrain.