IL-10 is an anti-inflammatory cytokine that regulates immune responses by reprogramming macrophage metabolism. This study shows that IL-10 inhibits glycolysis and promotes oxidative phosphorylation (OXPHOS) in macrophages, suppressing the mTOR pathway through the induction of the mTOR inhibitor DDIT4. This leads to mitophagy, which clears dysfunctional mitochondria with low membrane potential and high reactive oxygen species (ROS). In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria, leading to dysregulated NLRP3 inflammasome activation and increased IL-1β production. IL-10 also prevents mitochondrial dysfunction by maintaining mitochondrial integrity and function, which is essential for preventing excessive inflammation. The study demonstrates that IL-10 inhibits inflammasome activation by reducing mitochondrial ROS production and promoting mitophagy. In IL-10-deficient mice and IBD patients with IL-10R deficiency, aberrant inflammasome activation contributes to severe intestinal inflammation. These findings highlight the critical role of IL-10 in controlling inflammation through metabolic reprogramming of macrophages, particularly by inhibiting mTOR signaling and promoting mitochondrial clearance. Targeting the mTOR pathway in macrophages could be a therapeutic strategy for inflammatory diseases.IL-10 is an anti-inflammatory cytokine that regulates immune responses by reprogramming macrophage metabolism. This study shows that IL-10 inhibits glycolysis and promotes oxidative phosphorylation (OXPHOS) in macrophages, suppressing the mTOR pathway through the induction of the mTOR inhibitor DDIT4. This leads to mitophagy, which clears dysfunctional mitochondria with low membrane potential and high reactive oxygen species (ROS). In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria, leading to dysregulated NLRP3 inflammasome activation and increased IL-1β production. IL-10 also prevents mitochondrial dysfunction by maintaining mitochondrial integrity and function, which is essential for preventing excessive inflammation. The study demonstrates that IL-10 inhibits inflammasome activation by reducing mitochondrial ROS production and promoting mitophagy. In IL-10-deficient mice and IBD patients with IL-10R deficiency, aberrant inflammasome activation contributes to severe intestinal inflammation. These findings highlight the critical role of IL-10 in controlling inflammation through metabolic reprogramming of macrophages, particularly by inhibiting mTOR signaling and promoting mitochondrial clearance. Targeting the mTOR pathway in macrophages could be a therapeutic strategy for inflammatory diseases.