Recent studies have shown a rapid, robust, and lasting antidepressant effect of ketamine that makes ketamine a promising antidepressant drug. However, the mechanisms underlying this rapid antidepressant effect remain incompletely understood. The goal of the present study was to determine whether adenosine monophosphate-activated protein kinase (AMPK) was involved in ketamine's rapid antidepressant effect during the forced swimming test (FST). In the first stage of experiment, a lower level of phosphorylated form of AMPK (p-AMPK) in the hippocampus and a longer immobility time were observed in the depressed rats during FST; whereas ketamine reversed these changes at 30 min after the administration. In the second stage of experiment, we observed that, ketamine up-regulated the levels of p-AMPK and brain-derived neurotrophic factor (BDNF) in the hippocampus of the depressed rats. Moreover, AMPK agonist strengthened the antidepressant effect of ketamine with an up-regulation of BDNF, while AMPK antagonist attenuated the antidepressant effect of ketamine with a down-regulation of BDNF. In conclusion, our results suggest that the activation of AMPK in rat hippocampus is involved in the procedure of ketamine exerting rapid antidepressant effect through the up-regulation of BDNF.