Immune-responsive gene 1 (IRG1) is a multifunctional protein that mediates inflammatory responses in numerous pathological conditions. However, whether IRG1 has a relevance with osteoarthritis remains unaddressed. The inflammatory response of chondrocytes contributes to the progression of osteoarthritis. This study focused on assessing the functional link between IRG1 and interleukin-1beta (IL-1β)-elicited the inflammatory response of chondrocytes. The expression levels of IRG1 increased markedly in osteoarthritis cartilage compared to normal healthy cartilage. IRG1 level also increased after IL-1β stimulation in chondrocytes. The knockdown of IRG1 exacerbated IL-1β-elicited apoptosis and degradation of the extracellular matrix in chondrocytes. The nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation evoked by IL-1β stimulation was enhanced in IRG1-deficient chondrocytes. Importantly, restraint of the NLRP3 inflammasome was able to diminish IRG1-deficiency-amplified effects on IL-1β-stimulated chondrocytes. Additionally, the supplement of itaconate could ameliorate IL-1β-induced the inflammatory response of chondrocytes and reverse any IRG1-deficiency-induced effects. Altogether, our findings document a vital role for IRG1/itaconate in settling the inflammatory response of chondrocytes via effects on the NLRP3 inflammasome.