Objectives: To explore whether combined therapy with donepezil and acupuncture is better than treatment with donepezil or acupuncture individually in a rat model of Alzheimer’s disease. Methods: In this study, we randomly divided 40 7.5-month-old senescence-accelerated mouse prone 8 (SAMP8) male mice into four groups: SAMP8, SAMP8+D, SAMP8+MA and SAMP8+D+MA. An additional 10 7.5-month-old SAMR1 male mice were included as a healthy control group (SAMR1). Mice in the SAMP8+D group were given donepezil at a dose of 0.65 µg/g/day; mice in the SAMP8+MA group underwent manual acupuncture at GV20, GV26 and Yintang for 20 min per day; mice in the SAMP8+D+MA received both donepezil and manual acupuncture; and mice in the SAMR1 and SAMP8 groups underwent restraint only to control for the effects of handling. After the 15-day treatment, the Morris water maze test, micro-PET(positron-emission tomography), H&E (haematoxylin and eosin) staining, and immunohistochemistry were used to study the differences between donepezil (SAMP8+D), acupuncture (SAMP8+MA), and donepezil combined with acupuncture (SAMP8+D+MA) therapy for the treatment of Alzheimer’s disease. Results: We found that, compared with the untreated SAMP8 group, donepezil, manual acupuncture, and combined therapy with donepezil and manual acupuncture all improved spatial learning and memory ability, the level of glucose metabolism in the brain, and the content of Aβ amyloid in the cortex. Moreover, combined therapy outperformed treatment with donepezil or acupuncture individually in the SAMP8 mice. Conclusion: This study shows that the combination of manual acupuncture and donepezil in an Alzheimer’s disease animal model is superior to acupuncture and donezepil alone. However, randomised controlled trials should be undertaken to clarify the clinical efficacy of combination therapy.