Human tuberculosis (TB) is a leading global health threat and still constitutes a major medical challenge. However, mechanisms governing tissue pathology during post‐primary TB remain elusive, partly because genetically or immunologically tractable animal models are lacking. In human TB, the demonstration of a large relative increase in interleukin (IL)‐4 and IL‐13 expression, which correlates with lung damage, indicates that a subversive T helper (TH)2 component in the response to Mycobacterium tuberculosis (Mtb) may undermine protective immunity and contribute to reactivation and tissue pathology. Up to now, there has been no clear evidence regarding whether IL‐4/IL‐13‐IL‐4 receptor‐α (Rα)‐mediated mechanisms may in fact cause reactivation and pathology. Unfortunately, the virtual absence of centrally necrotizing granulomas in experimental murine TB is associated with a poor induction of a TH2 immune response. We therefore hypothesize that, in mice, an increased production of IL‐13 may lead to a pathology similar to human post‐primary TB. In our study, aerosol Mtb infection of IL‐13‐over‐expressing mice in fact resulted in pulmonary centrally necrotizing granulomas with multinucleated giant cells, a hypoxic rim and a perinecrotic collagen capsule, with an adjacent zone of lipid‐rich, acid‐fast bacilli‐containing foamy macrophages, thus strongly resembling the pathology in human post‐primary TB. Granuloma necrosis (GN) in Mtb‐infected IL‐13‐over‐expressing mice was associated with the induction of arginase‐1‐expressing macrophages. Indirect blockade of the endogenous arginase inhibitor l‐hydroxyarginine in Mtb‐infected wild‐type mice resulted in a strong arginase expression and precipitated a similar pathology of GN. Together, we here introduce an experimental TB model that displays many features of centrally necrotizing granulomas in human post‐primary TB and demonstrate that IL‐13/IL‐4Rα‐dependent mechanisms leading to arginase‐1 expression are involved in TB‐associated tissue pathology. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.