Introduction This study investigates drivers of childhood pulmonary tuberculosis (PTB) using a childhood ecosystem approach in South Africa. An ecosystem approach towards identifying risk factors for PTB may identify new directions for intervention. Methods Data were collected as part of a prospective cohort study of children presenting at a primary care facility or tertiary hospital with suspected TB. Characterization of the childhood ecosystem included proximal, medial and distal determinants. Proximal determinants included child characteristics that could impact PTB outcomes. Medial determinants included relational factors such as caregiver health that might impact interactions with the child. Distal determinants included macro-level determinants of disease such as socioeconomic status and food insecurity. Children started on TB treatment were followed for up to 6 months. Multivariate regression models tested independent associations between factors associated with PTB in children. Results Of 1,738 children enrolled in the study, 242 (20%) of children had confirmed PTB, 756 (63%) were started on TB treatment, and 444 (37%) had respiratory conditions other than TB. In univariate analyses, childhood malnutrition and caregiver smoking were associated with treated or confirmed PTB. In multivariate analyses, proximal factors such as male gender and hospitalization and low socio-economic status as a distal factor were associated with PTB. Conclusions Interventions may need to target subgroups of children and families at elevated risk for PTB. Screening for risk factors such caregiver health may guide targeting, and provision of social protection programs to bolster economic security may be important interventions for attenuating childhood exposure to risk factors.