Alveolar macrophages are the first immune cells to encounter Mycobacterium tuberculosis (Mtb) in the lungs, but they frequently fail to eliminate this pathogen, allowing Mtb to persist and replicate. Interstitial macrophages (IMs) are enlisted to restrict bacterial growth and limit immune evasion. While IMs have been implicated in controlling acute Mtb infection, their role during latent tuberculosis infection (LTBI) remains unexplored. To address this, we utilized a previously established mouse model of paucibacillary Mtb infection that recapitulates key aspects of human LTBI to deplete IMs during the latent phase. Depletion of IMs and recruited macrophages (RMs) led to TB relapse in 26% of mice compared to 2% in controls. Mice that relapsed exhibited an increased proportion of pro-inflammatory IMs and elevated concentrations of G-CSF, GM-CSF, IL-3, IL-12, IL-13, IL-17A, and KC in the lung. These findings demonstrate that IMs and RMs play a critical role in controlling latent Mtb and preventing TB relapse.