Despite significant progress, TB remains a major public health challenge in Southern Africa. We highlight the key initiatives in Eswatini, Mozambique and South Africa, which have implemented various interventions, including systematic TB screening, TB preventive treatment, targeted next-generation sequencing, targeted universal testing, and shorter drug-resistant and paediatric TB regimens. We also identify the key challenges, such as inconsistent drug access, increasing drug resistance and limited healthcare capacity, which continue to affect progress. Health systems must also balance TB care with broader healthcare priorities, and the integration of TB care into existing services requires further investment in outreach, treatment support and training. Identifying and treating missing people with TB, diagnosing TB in children, and improving treatment adherence remain critical areas requiring enhanced support and resources. While new diagnostic tools and treatments offer promise, their high costs and labour demands present barriers to routine implementation. Successful TB elimination will depend on simple, low-cost prevention, testing and treatment options, tailored to each country’s specific needs. All of which will require sustained political commitment, innovation and strategic investments in health system strengthening and community-based care.