The W-Beijing strain family is globally distributed and is associated with multidrug-resistant tuberculosis (TB) and treatment failure. Therefore, in this study, we examined the contribution of Toll-like receptor 2 (TLR2) to host resistance against Mycobacterium tuberculosis HN878, a clinical isolate belonging to the W-Beijing family. We show that TLR2 knockout (TLR2KO) mice infected with M. tuberculosis HN878 exhibit increased bacterial burden and are unable to control tissue-damaging, pulmonary neutrophilic inflammation. Consistent with a critical role for CXCL5 in regulating neutrophil influx, expression of epithelial cell-derived CXCL5 is significantly enhanced in TLR2KO mice prior to their divergence from wild-type (WT) mice in M. tuberculosis replication and neutrophilic inflammation. Depletion of neutrophils in TLR2KO mice by targeting Ly6G reverts lung inflammation and bacterial burden to levels comparable to those of WT mice. Together, the results establish that TLR2 controls neutrophil-driven immunopathology during infection with M. tuberculosis HN878 infection, likely by curtailing CXCL5 production.Keywords: CXCL5; Mycobacterium tuberculosis; TLR2; immunopathology; inflammation; neutrophils.