The present study aims to investigate the possibility of interaction of aspirin (Asp) or clopidogrel (CG) on donepezil (DP) hydrochloride in rats by HPLC-fluorescence detection. The separation of DP was achieved in ca. 13 min without interference of Asp and CG on the chromatogram. DP levels in rat plasma with a single administration of DP (5 mg/kg, i.p., group I) and those with a co-administration of Asp (200 mg/kg, p.o., group II or 200 mg/kg, i.p., group III) or CG (5 mg/kg, p.o., group IV) were monitored. The DP concentrations determined in rat plasma ranged from 25.0 to 336.1 ng/mL. Pharmacokinetic parameters for these groups were calculated and compared with one another. No significant difference was observed on the comparison of group I with other groups except for the mean resident time of group IV (p = 0.012). These basic findings may help clinical inference when DP is co-administered with Asp and CG to human.