Abstract Background Despite progress towards End TB Strategy targets for reducing tuberculosis (TB) incidence and deaths by 2035, South Africa remains among the top ten high-burden tuberculosis countries globally. A large challenge lies in how policies to improve detection, diagnosis and treatment completion interact with social and structural drivers of TB. Detailed understanding and theoretical development of the contextual determinants of problems in TB care is required for developing effective interventions. This article reports findings from the pre-implementation phase of a study of TB care in South Africa, contributing to HeAlth System StrEngThening in Sub-Saharan Africa (ASSET)—a five-year research programme developing and evaluating health system strengthening interventions in sub-Saharan Africa. The study aimed to develop hypothetical propositions regarding contextual determinants of problems in TB care to inform intervention development to reduce TB deaths and incidence whilst ensuring the delivery of quality integrated, person-centred care. Methods Theory-building case study design using the Context and Implementation of Complex Interventions (CICI) framework to identify contextual determinants of problems in TB care. Between February and November 2019, we used mixed methods in six public-sector primary healthcare facilities and one public-sector hospital serving impoverished urban and rural communities in the Amajuba District of KwaZulu-Natal Province, South Africa. Qualitative data included stakeholder interviews, observations and documentary analysis. Quantitative data included routine data on sputum testing and TB deaths. Data were inductively analysed and mapped onto the seven CICI contextual domains. Results Delayed diagnosis was caused by interactions between fragmented healthcare provision; limited resources; verticalised care; poor TB screening, sputum collection and record-keeping. One nurse responsible for TB care, with limited integration of TB with other conditions, and policy focused on treatment adherence contributed to staff stress and limited consideration of patients’ psychosocial needs. Patients were lost to follow up due to discontinuity of information, poverty, employment restrictions and limited support for treatment side-effects. Infection control measures appeared to be compromised by efforts to integrate care. Conclusions Delayed diagnosis, limited psychosocial support for patients and staff, patients lost to follow-up and inadequate infection control are caused by an interaction between multiple interacting contextual determinants. TB policy needs to resolve tensions between treating TB as epidemic and individually-experienced social problem, supporting interventions which strengthen case detection, infection control and treatment, and also promote person-centred support for healthcare professionals and patients. Graphic abstract