Neuropathic pain is caused by lesion or disease of the nervous system, which results in abnormal spontaneous and evoked pain. It’s common in clinical practice and greatly impairs the life quality of patients, but the effective treatment is still lacking. In this study, we aimed to explore the effect of quercetin (QUE) on neuropathic pain and the underlying mechanisms. Spinal nerve ligation (SNL) was performed in Sprague Dawley rats to establish the neuropathic pain model. Single or continuous oral administration of QUE after the operation or continuous administration before the operation was applied to evaluate the effects of QUE on SNL-induced thermal and cold hyperalgesia. Dorsal root ganglions from these rats were harvested to analyze the expression levels of some inflammatory mediators. Primary cultured astrocytes and HEK293 cells were used to further explore the downstream signaling pathways of QUE. Both single and continuous oral administration of QUE dose-dependently alleviated SNL-induced thermal and cold hyperalgesia. Pre-administration also attenuated neuropathic pain symptoms. Meanwhile, SNL-induced increase in protein or mRNA levels of some inflammatory mediators could be down-regulated by QUE treatment. Furthermore, QUE reduced the phosphorylation of TAK1, IKK and JNK2 in cultured astrocytes. Moreover, luciferase assay in HEK293 cells showed that QUE dose-dependently inhibited NF-κB activity only via TAK1. QUE exerts anti-inflammatory effects and alleviates neuropathic pain through the inhibition of Toll-like receptor signaling pathway. It could shed some light on the potential applications of QUE in chronic pain therapy.