Abstract: Objective To explore the impact of acute alcoholism on learning and memory of mice under stress conditions. Methods A total of 60 male Kunming mice were randomly divided into two groups (n=30): a stress group and a non-stress group. The stress group was exposed to stress stimuli for three consecutive days, while the non-stress group was placed in the same environment without stress stimuli. Afterward, mice from both groups were treated with either alcohol or normal saline, and divided into four groups (n=15): a non-stress normal saline group (C+V), a non-stress alcohol group (C+A), a stress normal saline group (S+V), and a stress alcohol group (S+A). The learning and memory of the mice were evaluated by the Morris water maze test, target location test, and novel object recognition test. The morphology and quantity of neurons in the hippocampal CA1 region were observed by hematoxylin-eosin (H-E) staining. The levels of N-methyl-D-aspartate receptor subunit 2A (NR2A) in the hippocampal CA1 region were measured by Western blot. Results Compared with the non-stress group, the stress group showed increases in the number of freezing behaviors and freezing percentage. In the Morris water maze test, the S+A group had a significantly longer escape latency and a significantly shorter time spent in the target quadrant and fewer crossings than the C+A group. In the target location and novel object recognition tests, the S+A group showed a significantly reduced discrimination index, compared with the C+A group. H-E staining results indicated that, compared with the C+A group, the S+A group exhibited severe edema and a markedly decreased number of neurons in the hippocampal CA1 region, with disorganized arrangement and even loss of neurons. Western blot results showed that NR2A expression in the hippocampal CA1 region of the S+A group significantly lower decreased, compared with those in the C+A group. Conclusions Stress alone or acute alcoholism can impair the learning and memory abilities of mice, and acute alcoholism under stress conditions exacerbates this damage.