Nontuberculous mycobacteria (NTM) infections are caused by environmental exposure. We describe spatial distribution of NTM infections and associations with sociodemographic factors and flooding in Missouri, USA. Our retrospective analysis of mycobacterial cultures reported to the Missouri Department of Health and Social Services surveillance system during January 1, 2008–December 31, 2019, detected geographic clusters of infection. Multilevel Poisson regression quantified small-area geographic variations and identified characteristics associated with risk for infection. Median county-level NTM infection rate was 66.33 (interquartile range 51–91)/100,000 persons. Risk of clustering was significantly higher in rural areas (rate ratio 2.82, 95% CI 1.90–4.19) and in counties with >5 floodings per year versus no flooding (rate ratio 1.38, 95% CI 1.26–1.52). Higher risk for NTM infection was associated with older age, rurality, and more flooding. Clinicians and public health professionals should be aware of increased risk for NTM infections, especially in similar environments.