β-hydroxybutyrate, a ketone body metabolite, has been shown to suppress depression-like behavior in rodents. In this study, we examined its antidepressive property in acute and chronic administration modes in mice by using forced swim test and tail suspension test. Results showed that the decrease effect of β-hydroxybutyrate (300 mg/kg) on immobility time in the tail suspension test and forced swim test in stress-naive mice began to be significant at day 11. In a dose-dependent experiment, β-hydroxybutyrate treatment (11 days) showed significant antidepressant activities at the dose of 200 and 300 mg/kg. Unlike fluoxetine, β-hydroxybutyrate treatment (300 mg/kg) showed no antidepressant activities in the acute (1 hour before the test) and three times administration mode within 24 hours (1, 5, and 24 hours before the test). But in a co-administration mode, β-hydroxybutyrate (100 mg/kg) -fluoxetine (2.5 mg/kg) co-administration exhibited an obvious antidepressant activity in the tail suspension test and forced swim test. Further analysis showed that the antidepressant effects of β-hydroxybutyrate and fluoxetine were not associated with the change in mouse locomotor activity. Furthermore, both chronic β-hydroxybutyrate treatment and β-hydroxybutyrate-fluoxetine co-treatment suppressed chronic unpredictable stress-induced increase in immobility time in the tail suspension test and forced swim test as well as chronic unpredictable stress-induced decrease in mouse body weight. Taken together, these results indicate that β-hydroxybutyrate (1) needs a relatively long time to show comparable behavioral activity to that of fluoxetine in assays that are sensitive to the behavioral effects of established antidepressant compounds and (2) can augment the antidepressant action of a sub-therapeutic dose of fluoxetine.