Pistacia lentiscus L. (Anacardeaceae), a largely distributed plant in the Mediterranean region, has long been used in human food, pharmaceutical industry and traditional medicine. P. lentiscus leaves are well known as a rich source of antioxidant polyphenols that may play a potential role in the prevention of neurodegeneration. Aluminium is a puissant neurotoxin metal; is proposed to be involved in the development of Alzheimer's disease (AD). The present study aims to examine the neuroprotective effect of P. lentiscus L. leaves extract (PL) on behavioral, histological and biochemical impairments caused by Al in male albinos mice. First, Al (100 ppm) and PL (150 and 300 ppm) were co-administered daily for two months to the mice. The extract significantly reversed all Al effects; it decreased the anxiety in head-dipping, black/ white and elevated plus maze tests, improved memory performance in Morris water maze test and inhibited histological alterations. On the other hand, in vitro study was added to determine the active principles of PL and to clarify their mode of action in the neuroprotective effect. The extract and its phenolic compounds (Myricetin rhamnoside, quercetin rhamnoside, gallic acid, myricetin and quercetin) were tested against Al-activated iron-induced lipid peroxidation in synaptosomal membrane. Results showed that PL and its bioactive compounds had a dose dependent effect where the highest effect was obtained with myricetin rhamnoside (IC50 = 0.04 mM). Therefore, PL is a source of phenolics possessing a neuroprotective potential which is validated by their ability to reverse the toxic effects caused by Al.Read less <