Recently, combination therapy involving cholinesterase (ChE) inhibitor with other neuroprotective agents has shown better desirable effect in the management/prevention of dementia but limited information is available on their effect with dietary polyphenols. Hence, this study sought to assess the combined pretreatment effect of curcumin, the major polyphenolic compound of turmeric (Curcuma longa) rhizomes, with donepezil, a cholinesterase inhibitor, on cognitive function in scopolamine-induced memory impairment in rats. Rats were pretreated with curcumin (50 mg/kg) and/or donepezil (2.5 mg/kg) via oral administration (p.o.) for seven successive days. Dementia was induced at the end of the treatment period by a single injection of scopolamine (1 mg/kg) via intraperitoneal (i.p.) administration. Thereafter, the changes in spatial and episodic memory were conducted; then, the estimation of some biochemical parameters associated with cognitive function was determined. Scopolamine-treated rats showed impaired learning and memory and increased activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), adenosine deaminase (ADA), and lipid peroxidation with a concomitant decreased in levels of nitric oxide (NO) and reduced glutathione (GSH), superoxide dismutase (SOD), and catalase activities when compared with control. However, combination of curcumin and donepezil improves learning and memory activity associated with inhibitory effect on AChE, BuChE, and ADA activities as compared to control. In addition, combined pretreatment significantly decreased lipid peroxidation and increased levels of NO and antioxidant status when compared with scopolamine-treated rats. This finding supports the concept that the combination strategy might be an alternative therapy in the management/prevention of neurological disorders. Thus, the observed anti-amnestic effect could be linked to their inhibitory effect on key enzyme of cholinergic system associated with memory function.