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Microglia-mediated neuroinflammation and synaptic damage contribute to the pathogenesis of major depressive disorder. Coeloglossum viride var. bracteatum extract (CE) has anti-inflammatory and neuroprotective effects. Therefore, we hypothesized that CE could inhibit the pathogenesis of depression. To test this hypothesis, we evaluated the antidepressant effects of CE in a lipopolysaccharide (LPS)-induced mouse model. We showed that CE ameliorated LPS-induced depressive-like phenotypes such as increased preference for sucrose, decreased immobility, and improved willingness to move in mice. Consistently, CE reduced the levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in the brain. Mechanistically, CE transformed the phenotypic polarization of microglia by inhibiting the enhancement of aerobic glycolysis and improving oxidative phosphorylation, mediated by the HIF-1α/PKM2 signaling axis. CE reversed the reduction in synaptic proteins, dendritic spines, and neuronal loss. Thus, CE may alleviate LPS-induced depression through anti-inflammation, alteration of microglial energy metabolism and protection of synaptic plasticity, thus highlighting its potential as antidepressant.