Nontuberculous mycobacteria (NTM) are ubiquitous bacteria that cause a spectrum of diseases, most notably pulmonary disease (NTMPD). The host factors contributing to the heightened susceptibility and severity of NTMPD in elderly individuals are poorly understood. Prior studies have reported increased incidence of NTMPD in individuals receiving immune modulatory biologics such as anti-TNF and JAK-STAT inhibitors. Moreover, we recently described that age-related changes in the lung microbiome, notably the loss of a main commensal species, may contribute to increased severity. Therefore, in this study we explore the hypothesis that TNF-inhibition and a disrupted lung microbiome are key factors that contribute to worse disease outcomes in older NTMPD patients. Young (4-6 years old) rhesus macaques were pretreated with nebulized amikacin and vancomycin to deplete the lung microbiome, pretreated with the TNF inhibitor Inflectra or left untreated. Animals were subsequently inoculated with subsp. (MAH) in the right lung. Bacterial load, radiographic changes, immune responses, and microbiome composition were monitored longitudinally. Antibiotic-treated animals experienced significant dysbiosis including the depletion of from the lung microbiome. One antibiotic-treated animal developed and resolved cavitary disease after the lung microbiome returned to homeostasis. Inflectra-treated animals favored an acute-phase response that persisted up to 114 days after inoculation and one Inflectra-treated animal developed chronic granulomatous disease. No control animals showed granulomas. These data suggest that lung microbiome dysbiosis and TNF inhibition can increase susceptibility to NTM granulomatous disease.