Osteoarthritis (OA) is a complex process, to which an inflammatory environment contributes markedly. Piceatannol exerts anti-inflammatory effects on several diseases. In the current study, we explored the protective effects of piceatannol on the progression of OA and investigated its molecular target. In vitro, piceatannol not only attenuated the over-production of inflammatory mediators and cytokines-such as nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6)-but also suppressed the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) at both the mRNA and protein levels. Piceatannol also decreased the expression of metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS5), which mediate extracellular matrix degradation. Mechanistically, we found that piceatannol inhibited IL-1β-induced nuclear factor kappa B (NF-κB) activation by activating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. Furthermore, piceatannol exerted protective effects in a mouse model of OA. Taken together, these findings indicate that piceatannol may be a potential therapeutic agent for OA.