It is well known that fluoride (F) poisoning causes anxiety and depression, and Agomelatine, an analogue of melatonin, has been reported to be effective on anxiety and depression. Therefore, the aim of this study is to investigate the short-term efficacy of Agomelatine application on anxiety and depression caused by F intoxication via Open-Field and Hot-Plate tests. Forty male BalB-C mice, aged 5-6 months, constituted the research material for this study. Subjects were randomly divided into 4 groups (Healthy-Control, Fluorosis-Control, 25 mg/kg Agomelatine, 50 mg/kg Agomelatine). Healthy-Control group (HC) received tap water, containing 0.3 ± 0.05 mgF/L. Fluorosis-Control group (F) received drinking water containing 40 mgF/L. Other two experimental groups (25 and 50) received drinking water containing 40 mgF/L and a single dose of Agomelatine (25 and 50 mg/kg respectively). The effect of Agomelatine on anxiety and depression induced by high dose F was evaluated using Open-Field and Hot-Plate tests compared to control groups. Fluorosis caused to decrease in Rearing, Grooming and Square numbers of Open-Field test and to increase Defecation counts (P<0.05). Agolematine applications enabled to normalize the Open-Field Test data. Similarly, according to the Hot-Plate findings, low reaction time caused by fluorosis increased in Agomelatine groups (P<0.05). According to those results, psychological improvement was observed in patients with fluorosis compared to the control group after Agomelatine applications. Consequently, according to Open-Field and Hot-Plate tests findings, it could be concluded that Agomelatine has a curative effect on anxiety and depression induced by F toxicity.