This study aimed to investigate the effects of long-term fluoride exposure on object recognition memory and mRNA expression of soluble N-ethylmaleimidesensitive fusion protein attachment protein receptors (SNARE) complex (synaptosome-associated protein of 25 kDa (SNAP-25), vesicle-associated membrane protein 2 (VAMP-2), and syntaxin 1A) in the hippocampus of male mice. Sixty sexually matured male Kunming mice were randomly divided into four groups: control group (given distilled water), low F group (25 mg/L NaF, corresponding to 11 mg/L F–), medium F group (50 mg/L NaF, corresponding to 22 mg/L F–), and high F group (100 mg/L NaF, corresponding to 45 mg/L F–). After 180 days, the spontaneous locomotor behavior and object recognition memory were detected by open field test and novel object recognition (NOR) test. Results showed that compared with the control group, frequency in each zone, total distance, and line crosses were significantly increased in low F and medium F groups, suggesting fluoride enhanced excitement of mice, while there were no marked changes in high F group. Twenty-four hours after training, a deficit of long-term memory (LTM) occurred only in high F group (P?<?0.05), but there was no significant change of short-term memory (STM) 1.5 h later. The mRNA expression levels of SNAP-25, VAMP-2, and syntaxin 1A were detected by real-time quantitative RT-PCR, which revealed that the mRNA expression of VAMP-2 was significantly increased in medium F and high F groups (P?<?0.01). Taken together, these results indicated that long-term fluoride administration can enhance the excitement of male mice, impair recognition memory, and upregulate VAMP-2 mRNA expression, which are involved in the adverse effects of fluoride on the object recognition memory of nervous system.