Acute gouty arthritis (AGA) is an inflammatory disease caused by deposition of monosodium urate (MSU) crystals in joints, leading to severe inflammatory responses. Although current treatments such as non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids relieve symptoms, their clinical use is limited by adverse effects including gastrointestinal irritation, renal toxicity, and cardiovascular complications. Therefore, safer and more effective therapeutic strategies are required. CPS-57 is a natural compound derived from cyanogenic natural products used in traditional East Asian medicine. Previous studies have reported that CPS-57 exhibits immunomodulatory and anti-inflammatory activities, including suppression of inflammatory cytokine production, attenuation of oxidative stress–induced cellular damage, and regulation of cell death pathways. In this study, we investigated the anti-inflammatory effects of CPS-57 in an AGA model induced by lipopolysaccharide (LPS) and MSU. Our results showed that CPS-57 significantly reduced LPS and MSU-induced inflammatory responses. In THP-1 macrophages, CPS-57 decreased mitochondrial DNA (mtDNA) release from damaged mitochondria and suppressed AIM2 inflammasome–associated inflammatory cell death. These findings suggest CPS-57 alleviates excessive inflammation by regulating mtDNA release and AIM2 inflammasome activation, indicating its potential as a therapeutic candidate for AGA and related inflammatory diseases.