Purpose: To determine the inhibitory effect of curcumin on the expression of brain-derived neurotrophic factor (BDNF) in hippocampus of mice with sleep deprivation. Methods: Expressions of BDNF and miRNA-206 were evaluated using quantitative real time-polymerase chain reaction (qRT-PCR) in a sleep-deprived mouse model. Interaction of BDNF and miRNA-206 was assessed by dual luciferase and qPCR) assays. The effect of curcumin on BDNF and miRNA-206 was also determined by qRT-PCR. Results: Expressions of BDNF and miRNA-206 were significantly suppressed in hippocampus of mice in sleep deprivation group compared with control mice (p < 0.05). Treatment with miRNA-206 significantly suppressed the luciferase activity of wild type (WT) BDNF reporter gene vector (p < 0.05) rather than the mutated (mut) vectors. Inhibition of miRNA-206 upregulated RNA and protein levels of BDNF (p < 0.05), while curcumin treatment inhibited BDNF expression (p < 0.01) and upregulated miRNA-206 level (p < 0.01). Conclusion: Curcumin inhibits BDNF expression by upregulating miRNA-206 level in hippocampus tissues of mice in the sleep deprivation model. The relationship between BDNF and miRNA-206 might provide a new direction for the development of new therapeutics for sleep deprivation.