Osteoarthritis (OA) is a heterogeneous disease involving the whole joint. The pathogenesis involves oxidative stress levels and chronic inflammation, and Valencene (VA) has excellent anti-inflammatory and antioxidant stress abilities.The objective was to study the effects of VA therapy on combating oxidative stress and to evaluate the protective effect of chondrocytes to alleviate the progression of OA.C57BL6J mouse chondrocytes were used as the primary cells in this study. Mouse chondrocytes were stimulated with IL-1β, and VA was administered in different concentrations. Reactive oxygen species (ROS) assay kits, western blotting, cellular immunofluorescence, and scanning microscopy were used to evaluate VA's antioxidant stress mechanism, anti-inflammatory effect, and cartilage protective ability. The mouse arthritis model constructed by destabilization of medial meniscus (DMM) was observed by micro-CT scan and histology after different treatments.We found that VA can reverse the rise of ROS under IL-1β, the degeneration of the cartilage extracellular matrix, and the production of inflammatory mediators. In terms of mechanism, VA activated NRF2/HO-1/NQO1 pathway, thus enhancing ROS clearance. The phosphorylation of IκBα is inhibited, which further reduces the downstream phosphorylation of P65 in nuclear factor-κB (NF-κB) signaling. In addition, VA inhibited mitogen-activated protein kinase (MAPK) signaling molecules P-JNK, P-ERK, and P-P38, inhibiting the production of inflammatory mediators and thus inhibiting Aggrecan and Collagen Type II （COL2）degeneration. In vivo, VA reduced DMM-induced osteophytes and spurs, suppressed subchondral bone destruction, and reduced articular cartilage erosion.Our study demonstrated that VA is an effective candidate for OA treatment.Copyright © 2023. Published by Elsevier B.V.