Abstract Thymic regeneration is a crucial function that allows for renewal of immune competance after stress, infection or immunodepletion, however the mechanisms governing this rejuvenation remain poorly understood. Here we detail a framework of endogenous thymic regeneration centred on IL-22, a recently identified cytokine primarily implicated in maintenance of epithelial barrier function. Although IL-22 was redundant for steady-state thymopoiesis, thymic recovery was impaired in IL-22-deficient mice and intrathymic levels of IL-22 were significantly increased in WT mice following thymic damage. IL-22, which signalled through thymic epithelial cells and promoted their proliferation and survival, was upregulated by radio-resistant RORγ(t)+NKp46-CCR6+ lymphoid tissue-inducer cells after thymic injury under the control of dendritic cell-derived IL-23 and triggered by the depletion of CD4+CD8+ double positive (DP) thymocytes. Importantly, administration of IL-22 enhanced thymic recovery following irradiation damage. These studies reveal a network of endogenous thymus regeneration where 1) the depletion of DP thymocytes triggers 2) upregulation of IL-23 by DCs that induces 3) the production of IL-22 by thymic LTi. This cascade of events leads to regeneration of the epithelial microenvironment and, ultimately, to rejuvenation of thymopoiesis; presenting an innovative strategy for improving immune competence in patients whose thymus has been damaged from infection or cytoreductive therapy.