Severity of pulmonary viral infections, including influenza A virus (IAV), is linked to excessive immunopathology, which impairs lung function. Thus, the same immune responses that limit viral replication can concomitantly cause lung damage that must be countered by largely uncharacterized disease tolerance mechanisms. Here, we show that mitochondrial cyclophilin D (CypD) protects against IAV via disease tolerance. CypD−/− mice are significantly more susceptible to IAV infection despite comparable antiviral immunity. This susceptibility results from damage to the lung epithelial barrier caused by a reduction in interleukin-22 (IL-22)-producing natural killer (NK) cells. Transcriptomic and functional data reveal that CypD−/− NK cells are immature and have altered cellular metabolism and impaired IL-22 production, correlating with dysregulated bone marrow lymphopoiesis. Administration of recombinant IL-22 or transfer of wild-type (WT) NK cells abrogates pulmonary damage and protects CypD−/− mice after IAV infection. Collectively, these results demonstrate a key role for CypD in NK cell-mediated disease tolerance. Display omitted •Mitochondrial CypD is required to protect against severe influenza infection•CypD expression promotes NK cell lymphopoiesis and maturation•NK cell-derived IL-22 enhances disease tolerance during influenza infection•Transfer of WT NK cells confers protection in CypD−/− mice to influenza infection Downey et al. show that CypD is critical in immunity to influenza A virus (IAV) infection by promoting disease tolerance. CypD regulates NK cell hematopoiesis in the bone marrow and the accumulation of mature IL-22-producing NK cells in the airways, which protect the pulmonary epithelium from IAV-induced damage.