Accumulating evidence suggests that the gut microbiota-brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action.