Currently, mesenchymal stem cells (MSCs) based therapy has extensive attraction for Alzheimer’s disease (AD). However, low survival rate of MSCs after transplantation is a huge challenging. The current study aimed to improve adipose-derived MSCs (AD-MSCs)-based therapy by their pre-treatment with melatonin (MT) ‘a well-known antioxidant’ in an animal model of AD. In this study, after isolating rat AD-MSCs from the epididymal white adipose tissues, the cells were pretreated with 5μM of MT for 24 hours. Forty male Wistar rats were randomly allocated to control, sham, amyloid-beta (Aβ) peptide, AD-MSCs and MT-pretreated ADMSCs groups. The novel object recognition, passive avoidance test, Morris water maze and open field test were performed two months following the cell transplantation. The rats were sacrificed 69 days following cell therapy. The brain tissues were removed for histopathological analysis and also immunohistochemistry was performed for two Aβ1-42 and Iba1 proteins. It has been revealed that both AD-MSCs and MT-AD-MSCs migrated to brain tissues after intravenous transplantation. However, MT-ADMSCs significantly improved learning, memory and cognition compared with AD-MSCs (P<0.05). Furthermore, clearance of Aβ deposition and reduction of microglial cells were significantly increased in the MT-ADMSCs compared with AD-MSCs. Although stem cell therapy has been introduced as a promising strategy in neurodegenerative diseases, however, its therapeutic properties are limited. It is suggested that pretreatment of MSCs with melatonin partly would increase the cells efficiency and consequently could decrease AD complication including memory and cognition.