Kaempferol (KA), a widely recognized anti-oxidation and anti-inflammation agent, has been reported to have neuroprotective effects. This work aimed to investigate whether KA protects mouse dorsal root ganglia (DRG) neurons against bupivacaine (BU)-stimulated neurotoxicity and explore the underlying mechanisms. In this study, BU treatment suppressed DRG neuron viability and promoted LDH leakage, which was partially abated by KA. Besides, BU-triggered DRG neuron apoptosis, and changes in Bax and Bcl-2 levels were attenuated by KA treatment. In addition, pretreatment with KA substantially reduced interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α levels in BU-treated DRG neurons. In addition, KA administration abrogated BU-induced decline in CAT, SOD, and GSH-Px levels, as well as the increase in the malondialdehyde level. Interestingly, we found that KA significantly attenuated BU-induced TNF receptor-associated factor 6 (TRAF6) upregulation as well as NF-κB activation. Furthermore, oe-TRAF6-mediated TRAF6 overexpression promoted NF-κB activation and partly abolished KA-induced protection against BU-triggered neurotoxic effects on DRG neurons. Our results revealed that KA mitigated BU-induced neurotoxic effects on DRG neurons by deactivating the TRAF6/NF-κB signaling.