Depression is highly prevalent in patients suffering from chronic inflammatory diseases. Dysregulated neuroinflammation and concomitant-activated microglia play a pivotal role in the pathogenesis of depression. As one of the biologically functional phytochemicals in soybeans, soy isoflavones (SI) have been reported to exhibit anti-inflammatory, antioxidant, estrogen-like and neuroprotective activities. However, there is no research on how SI administration affects the depressive-like behavior induced by neuroinflammation. Therefore, this study was conducted to evaluate the antidepressant-like action of SI in acute lipopolysaccharide (LPS)-treated mice and to explore its underlying mechanisms. An open field test, a sucrose preference experiment, a tail suspension test and a forced swimming task were conducted to assess the influence of SI on the depressive-like behavior induced by LPS injection. Then, the levels of the pro-inflammation cytokines, tryptophan (Trp) metabolism in the cortex and hippocampus, and the synaptic plasticity-related signal pathway in the hippocampus, which are involved in the pathophysiology of depression, were examined. The results showed that SI administration remarkably alleviated LPS-induced depressive-like behavior as indicated by the increased sucrose preference index and the decreased immobility time both in the tail suspension test and the forced swimming task. SI significantly suppressed neuroinflammation in the hippocampus of LPS mice, as indicated by a decrease in the levels of interleukin (IL)-1β, IL-10, tumor necrosis factor (TNF-α) and suppression of the signal pathway of TLR4/NF-κB. Additionally, SI administration regulated tryptophan (Trp) metabolism by increasing 5-hydroxytryptamine (5-HT) levels, inhibiting the release of kynurenine (KYN) in the cortex and hippocampus, and elevating the expressions of synaptic plasticity-related protein markers such as postsynaptic density-95 (PSD-95) and synaptophysin (SYN). The current study demonstrated that soy isoflavones could reverse LPS-induced depressive-like behavior by suppressing neuroinflammation, normalizing the Trp metabolism, up-regulating the expressions of synaptic plasticity-related proteins, and inhibiting the TLR4/NF-κB pathway activation in the hippocampus of mice, exerting their antidepressant-like action.