Interleukin 10 (IL-10) is a critical anti-inflammatory cytokine that plays a crucial role in controlling immune responses. However, its mechanisms of action remain poorly understood. This study demonstrates that IL-10 opposes the metabolic switch induced by inflammatory stimuli in macrophages. Specifically, IL-10 inhibits lipopolysaccharide (LPS)-induced glucose uptake and glycolysis, promoting oxidative phosphorylation. IL-10 also suppresses mammalian target of rapamycin (mTOR) activity through the induction of DDIT4, an mTOR inhibitor. Consequently, IL-10 promotes mitophagy, which eliminates dysfunctional mitochondria characterized by low membrane potential and high levels of reactive oxygen species (ROS). In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in a mouse model of colitis and inflammatory bowel disease (IBD) patients, leading to dysregulated activation of the NLRP3 inflammasome and production of IL-1β. The study reveals that IL-10 maintains mitochondrial integrity and function by inhibiting mTOR signaling, and that this metabolic control is essential for controlling inflammation. Defects in this regulation, such as enhanced or prolonged mTORC1 activation, can result in abnormal metabolic changes and loss of mitochondrial integrity, contributing to severe intestinal inflammation in IBD. Therapeutic targeting of the mTORC1 pathway in macrophages could be beneficial for treating or preventing inflammatory diseases.Interleukin 10 (IL-10) is a critical anti-inflammatory cytokine that plays a crucial role in controlling immune responses. However, its mechanisms of action remain poorly understood. This study demonstrates that IL-10 opposes the metabolic switch induced by inflammatory stimuli in macrophages. Specifically, IL-10 inhibits lipopolysaccharide (LPS)-induced glucose uptake and glycolysis, promoting oxidative phosphorylation. IL-10 also suppresses mammalian target of rapamycin (mTOR) activity through the induction of DDIT4, an mTOR inhibitor. Consequently, IL-10 promotes mitophagy, which eliminates dysfunctional mitochondria characterized by low membrane potential and high levels of reactive oxygen species (ROS). In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in a mouse model of colitis and inflammatory bowel disease (IBD) patients, leading to dysregulated activation of the NLRP3 inflammasome and production of IL-1β. The study reveals that IL-10 maintains mitochondrial integrity and function by inhibiting mTOR signaling, and that this metabolic control is essential for controlling inflammation. Defects in this regulation, such as enhanced or prolonged mTORC1 activation, can result in abnormal metabolic changes and loss of mitochondrial integrity, contributing to severe intestinal inflammation in IBD. Therapeutic targeting of the mTORC1 pathway in macrophages could be beneficial for treating or preventing inflammatory diseases.