Pelargonidin (PG), a derivative of anthocyanins, has anti-oxidant and anti-inflammatory properties. Herein, the protective effect and the mechanism of PG in counteract the osteoarthritis (OA) progression were needed to further evaluate. In the current study, C57BL/6 mice was induced by destabilization of medial meniscus (DMM) surgery to establish the OA model. Primary chondrocytes were acquired from the knee cartilage of newborn mice. Then, PG was administrated to OA mice and IL-1β-stimulated chondrocytes to evaluate its protective effects, respectively. Results uncovered that no conspicuous cytotoxic effects were observed when chondrocytes were treated with PG at a concentration lower than 40 μM for 24–72 h. Thus, 10 μM, 20 μM, and 40 μM PG were chosen for subsequent experiments in vitro. Then, we observed that 10, 20, and 40 μM PG reduced the levels of IL-6, TNF-α, COX-2 and iNOS in chondrocytes. In line, PG inhibited the IL-1β-induced ECM catabolism in chondrocytes, as evidenced by deepening toluidine blue staining, increased expression of Collagen II, and decreased expressions of ADAMTS5 and MMP13. Moreover, PG also reduced the IL-1β-stimulated p-p65 overexpression and nuclear translocation of p65 in chondrocytes. In vivo, Safranin O/Fast green and HE staining showed that articular cartilage surface morphology was basically smooth and complete after PG treatment for 8 weeks. Similarly, OARSI scores and MMP13 expression were apparently decreased, whereas Aggrecan expression was elevated in PG-treated mice 8 weeks after DMM surgery. In conclusion, PG can effectively ameliorate inflammatory reactions and cartilage degeneration via suppressing the NF-κB pathway, thereby restraining the OA progression.