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Arthritis can be defined as a painful musculoskeletal disorder that affects the joints. Hesperidin methyl chalcone (HMC) is a flavonoid with analgesic, anti-inflammatory, and antioxidant effects. However, its effects on a specific cell type and in the zymosan-induced inflammation are unknown. We aimed at evaluating the effects of HMC in a zymosan-induced arthritis model. A dose-response curve of HMC (10, 30, or 100 mg/kg) was performed to determine the most effective analgesic dose after intra-articular zymosan stimuli. Knee joint oedema was determined using a calliper. Leukocyte recruitment was performed by cell counting on knee joint wash as well as histopathological analysis. Oxidative stress was measured by colorimetric assays (GSH, FRAP, ABTS and NBT) and RT-qPCR (gp91 phox and HO-1 mRNA expression) performed. In vitro, oxidative stress was assessed by DCFDA assay using RAW 264.7 macrophages. Cytokine production was evaluated in vivo and in vitro by ELISA. In vitro NF-κB activation was analysed by immunofluorescence. We observed HMC reduced mechanical hypersensitivity and knee joint oedema, leukocyte recruitment, and pro-inflammatory cytokine levels. We also observed a reduction in zymosan-induced oxidative stress as per increase in total antioxidant capacity and reduction in gp91 phox and increase in HO-1 mRNA expression. Accordingly, total ROS production and macrophage NFκB activation were diminished. HMC interaction with NFκB p65 at Ser276 was revealed using molecular docking analysis. Thus, data presented in this work suggest the usefulness of HMC as an analgesic and anti-inflammatory in a zymosan-induced arthritis model, possibly by targeting NFκB activation in macrophages.