Cognitive deficiency and oxidative stress have been well documented in aging disorders including Alzheimer’s disease. The aim of this study was to investigate the therapeutic efficacy of Caralluma tuberculata methanolic extract (CTME) on cognitive impairment in mice induced with d-galactose. In this study we assessed the therapeutic efficacy of CTME on cognitive impairment in mice induced with d-galactose by conduction of behavioral and cognitive performance tests. In order to explore the possible role of CTME against d-galactose-induced oxidative damages, various biochemical indicators were assessed. Chronic administration of d-galactose (150mg/kgd, s.c.) for 7 weeks significantly impaired cognitive performance (in step-through passive, active avoidance test, Hole-Board test, Novel object recognition task and Morris water maze) and oxidative defense as compared to the control group. The results revealed that CTME treatment for two weeks (100, 200 and 300mg/kg p.o) significantly ameliorated cognitive performance and oxidative defense. All groups of CTME enhanced the learning and memory ability in step-through passive, active avoidance test, Hole-Board test Novel object recognition task and Morris water maze. Furthermore, high and middle level of CTME (300 and 200mg/kg p.o) significantly increased Total antioxidative capacity (T-AOC), Glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity, neprilysin (NEP), and β-site AβPP cleaving enzyme 1 (BACE1) expression while Nitric Oxide (NO), Nitric Oxide Synthase (NOS) activity and Malondialdehyde (MDA) concentration, and the level of Aβ1-42 and presenilin 1 (PS1) were decreased. The present study showed that CTME have a significant relieving effect on learning, memory and spontaneous activities in d-galactose-induced mice model, and ameliorates cognitive impairment and biochemical dysfunction in mice.