Calyptrochilum emarginatum (Afzel. Ex Sw.) Schltr. (Orchidaceae) is a traditional medicinal plant known for its antimicrobial properties and efficacy in managing convulsive fever and menstrual disorders and addressing conditions such as malaria, tuberculosis, and cough. The study aims to examine the memory-enhancing and neuroprotective properties of ethanol extract of Calyptrochilum emarginatum leaves (EECEL) in scopolamine-induced amnesia mice model. Forty-two male mice were divided into six groups (n=7). Group 1 served as control, administered distilled water (10mL/kg, p. o), group 2 received scopolamine only (3mg/kg, i. p.), groups 3 to 6 received pretreatments of EECEL (50, 100, and 200mg/kg, p. o.) and donepezil (1mg/kg, p. o.) 30min before scopolamine (3mg/kg), for seven days. Following treatments, behavioral (learning and memory) assessments were carried out, while biochemical (acetylcholinesterase activity, oxidative stress markers, inflammatory cytokines markers) and histological evaluations were done after euthanasia. Scopolamine significantly impaired spatial, long term and recognition memory. Nevertheless, administration of EECEL (50, 100, and 200mg/kg orally) enhanced memory function in mice, as observed in the Y maze [F (5, 30)=20.23, p<0.0001], Morris water maze [F (10, 90)=3.105, p=0.0019; [F (5, 30)=21.13, p<0.0001]], and novel object recognition tasks [F (5, 30)=37.22, p<0.0001)]. Scopolamine-treated mice exhibited significant dysfunction in the cholinergic system, as evidenced by elevated AChE activity [0.099±0.005 vs. 0.063±0.004mol/min/g] with an elevation in oxidative stress. On the other hand, administration of EECEL counteracted these consequences by reducing AChE activity, mitigating oxidative damage, reducing pro-inflammatory cytokines, and preventing degeneration of neurons. The results demonstrated that EECEL effectively mitigates scopolamine-induced memory impairment via an oxido-inflammatory mechanism and modulation of the central cholinergic system.