AbstractDonepezil (DPZ) is a reversible cholinesterase inhibitor used to treat Alzheimer's disease (AD), while with disadvantages such as gastrointestinal side effects after oral administration and poor adherence in the elderly. The purpose of this study was to develop a thermosensitive hydrogels loaded with donepezil nanosuspension (DPZ‐NS‐gel) for transnasal administration to improve brain targeting and reduce peripheral toxicity. The results of powder X‐ray diffraction and differential scanning calorimeter showed that the crystal type of DPZ changed from form II to form C during the grinding process. DPZ‐NS‐gel was obtained by mixing DPZ‐NS into the blank thermosensitive hydrogel constructed with poloxamer 407 and poloxamer 188. DPZ‐NS‐gel was in sol state at 25 °C and formed gel at 33 °C. Compared with DPZ‐NS, the in vitro release of DPZ‐NS‐gel showed the sustained release profile. In vivo studies indicated that DPZ‐NS‐gel by nasal administration may increase the amount of drug entering into the brain. The in vivo safety evaluation showed no severe inflammatory response and pathological change when DPZ‐NS‐gel was administered by nasal administration. This study provided a promising strategy for clinical application in improving the bioavailability of DPZ in the brain, avoiding oral‐induced gastrointestinal side effects and improving medication adherence in the elderly.