Inflammatory damage contributes to beta cell failure in type 1 and 2 diabetes (T1D and T2D, respectively). Mitochondria are damaged by inflammatory signaling in beta cells, resulting in impaired bioenergetics and initiation of proapoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here, we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent beta cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic proinflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient II cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased beta cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human beta cell apoptosis. Thus, mitophagy promotes ti cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent beta cell failure in diabetes and may be beneficial in other inflammatory conditions.