In recent years, the prevalence, mental disability, and suicide rates of depression have been increasing without a corresponding significant change in cure rate, making depression the second largest disease burden worldwide. There is an urgent need to find more effective drugs and other therapeutic strategies. Accumulating evidence has revealed that ketamine elicits a fast-acting and sustained antidepressant effect, but the potential mechanisms underlying its antidepressant effects are not yet fully clear. Previous studies have indicated that ketamine’s mechanism of action involves the inhibition of presynaptic and postsynaptic N-methyl-d-aspartate receptors (NMDARs) in GABAergic interneurons and the activation of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and the brain-derived neurotrophic factor-tyrosine kinase receptor B (BDNF-TrkB) signaling pathway. Additionally, there is growing evidence that the gut microbiota may play a crucial role in the antidepressant effects of ketamine. In this chapter, we will discuss recent findings regarding the correlation between gut microbiota and the antidepressant effects of ketamine and their potential mechanisms of action. Further understanding of these pathways will likely lead to the development of novel and more effective treatments for depression. © Springer Nature Singapore Pte Ltd. 2020.