While essentially all individuals infected by Mycobacterium tuberculosis (Mtb) mount a robust immune response to the pathogen, the specific mechanisms that differentiate protection from disease remain unclear. Protective immunity to TB requires T cell-derived interferon gamma (IFN-g), which induces the production of nitric oxide (NO) in macrophages. Animals lacking either of these factors suffer from severe TB disease characterized by high bacterial loads and granulocytic inflammation. Since NO can kill Mtb in axenic culture, most models of protective immunity posit that this mediator primarily acts by inhibiting bacterial replication, which limits the subsequent inflammatory tissue damage. In contrast, we report NO primarily protects mice by inhibiting interleukin-1 (IL-1) processing and secretion by the Caspase-1 inflammasome. This activity suppresses an IL-1 and 12/15-lipoxygenase dependent neutrophil recruitment cascade that promotes bacterial replication. Using Mtb mutants as indicators of the pathogen’s environment, we inferred that granulocytic inflammation generates a nutrient-replete niche that promotes Mtb replication in multiple susceptible mouse strains. Parallel clinical studies indicate that a similar inflammatory pathway promotes TB in patients. The abundance of IL-1b and 12-LOX products correlate with the number of airway neutrophils, bacterial burden, and lung pathology, and genetic polymorphisms that increase the expression of these genes are associated with TB risk. We propose that Mtb exploits neutrophilic inflammation to preferentially replicate at sites of tissue damage that promote contagion.