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Disrupted mitochondrial function and reactive oxygen species (ROS) generation cause cellular damage and oxidative stress‐induced macrophage inflammatory cell death. It remains unclear how mitochondrial dysfunction relates to inflammasome activation and pyroptotic cell death. In this study, we demonstrated that tumor necrosis factor receptor‐associated factor 3 (TRAF3) regulates mitochondrial ROS production and promotes TLR agonist LPS plus nigericin (LPS/Ng)‐induced inflammasome and pyroptosis in mouse primary macrophages and human monocyte THP‐1 cells. Co‐IP assays confirmed that TRAF3 forms a complex with TRAF2 and cIAP1 and mediates ubiquitin and degradation of Unc‐51 like autophagy activating kinase 1 (ULK1). Moreover, knockdown of ULK1 in THP‐1 cells significantly promoted LPS/Ng‐induced inflammasome by activating caspase 1 and mature IL‐1β. Apoptosis inducing factor (AIF) translocation from mitochondrial to nuclear was observed in ULK1‐deficient THP‐1 cells under LPS/Ng stimulation, which mediates LPS/Ng‐induced cell death in ULK1 deficient macrophages. In conclusion, this study identified a novel role of TRAF3 in regulation of ULK1 ubiquitination and inflammasome signaling and provided molecular mechanisms by which ubiquitination of ULK1 controls mitochondrial ROS production, inflammasome activity, and AIF‐dependent pyroptosis. [ABSTRACT FROM AUTHOR]