Osteoarthritis (OA) is a degenerative disease of joints, which is closely associated with cartilage degradation. Eriodictyol, a natural flavonoid compound, has been reported to have anti-inflammatory and anti-osteoclastogenic effects. However, the effect of eriodictyol on inflammatory response in OA has not been investigated. Our results showed that eriodictyol attenuated the inhibition of cell viability in IL-1β-stimulated chondrocytes. In addition, eriodictyol inhibited the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and the production of prostaglandin E2 (PGE2) and nitric oxide (NO), which were induced by IL-1β. The induction of inflammatory cytokines and matrix metalloproteinases (MMPs) caused by IL-1β stimulation was also attenuated by eriodictyol. Furthermore, eriodictyol pretreatment inhibited IκBα degradation and the level of p-p65, and enhanced the up-regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) in IL-1β-stimulated chondrocytes. Si-Nrf2 treatment significantly inhibited the expressions of Nrf2 and HO-1 in chondrocytes. Additionally, si-Nrf2 transfection also abolished the anti-inflammatory effects of eriodictyol in chondrocytes. These findings indicated that eriodictyol exhibited anti-inflammatory effect in IL-1β-stimulated chondrocytes. The effect was mediated by inhibiting NF-κB via activating the Nrf2/HO-1 signaling pathway.