Gout arthritis is a painful inflammatory disease induced by monosodium urate (MSU) crystals. We evaluate the therapeutic potential of the flavonoid hesperidin methylchalcone (HMC) in a mouse model of gout arthritis induced by intra-articular injection of MSU (100 μg/10 μL). Orally given HMC (3-30 mg/kg, 100 μL) reduced in a dose-dependent manner the MSU-induced hyperalgesia (44%, p < 0.05), edema (54%, p < 0.05), and leukocyte infiltration (70%, p < 0.05). HMC (30 mg/kg) inhibited MSU-induced infiltration of LysM-eGFP+ cells (81%, p < 0.05), synovitis (76%, p < 0.05), and oxidative stress (increased GSH, FRAP, and ABTS by 62, 78, and 73%, respectively; reduced O2- and NO by 89 and 48%, p < 0.05) and modulated cytokine production (reduced IL-1β, TNF-α, IL-6, and IL-10 by 35, 72, 37, and 46%, respectively, and increased TGF-β by 90%, p < 0.05). HMC also inhibited MSU-induced NF-κB activation (41%, p < 0.05), gp91phox (66%, p < 0.05) and NLRP3 inflammasome components mRNA expression in vivo (72, 77, 71, and 73% for NLRP3, ASC, pro-caspase-1, and pro-IL-1 β, respectively, p < 0.05), and induced Nrf2/HO-1 mRNA expression (3.9- and 5.1-fold increase, respectively, p < 0.05). HMC (30, 100, and 300 μM) did not inhibit IL-1β secretion by macrophages primed by LPS and challenged with MSU (450 μg/mL), demonstrating that the anti-inflammatory effect of HMC in gout arthritis depends on inhibiting NF-κB but not on direct inhibition of inflammasome. The pharmacological effects of HMC indicate its therapeutic potential for the treatment of gout.