Osteoarthritis (OA) is an age-related joint degenerative disease associated with pain, joint deformity, and disability. The disease starts with cartilage damage but then progressively involves subchondral bone, causing an imbalance between osteoclast-driven bone resorption and osteoblast-driven remodeling. Here, we summarize the data for the role of oxidative stress and inflammation in OA pathology and discuss how these two processes are integrated during OA progression, as well as their contribution to abnormalities in cartilage/bone metabolism and integrity. At the cellular level, oxidative stress and inflammation are counteracted by transcription factor nuclear factor erythroid p45–related factor 2 (NRF2), and we describe the regulation of NRF2, highlighting its role in OA pathology. We also discuss the beneficial effect of some phytonutrients, including the therapeutic potential of NRF2 activation, in OA.