In response to the global pandemic of COVID-19, South Africa implemented a strict lockdown in March 2020 before its first COVID-19 wave started, gradually lifted restrictions between May and September 2020, and then re-imposed restrictions in December 2020 in response to its second wave. There is concern that COVID-19-related morbidity and mortality, the deprioritization of TB activities, fear of transmission, and societal restrictions led to a reduction in tuberculosis (TB) treatment initiations. We analysed monthly public sector, facility-level data from South Africa’s District Health Information System (DHIS) from January 2019 to April 2021 to quantify changes in TB treatment initiation numbers stratified by province, setting, and facility type and compared the timing of these changes to COVID-19 case numbers and government lockdown levels. At the 1189 facilities that reported observations for all 28 months of our study period, TB treatment initiations in 2020 were 20.4% lower than in 2019 and 21.9% lower in the first four months of 2021 than in 2019. At the 3669 facilities that reported observations in ≤28 months, numbers of TB treatment initiations declined sharply in all provinces in May-August 2020, compared to the same months in 2019. After recovering somewhat in the last four months of 2020, numbers plummeted again in early 2021. Percentage reductions were somewhat larger in urban and peri-urban areas than in rural areas. Most provinces experienced a clear inverse relationship between COVID-19 cases and TB treatment initiations but little relationship between TB treatment initiations and lockdown level. The COVID-19 pandemic and responses to it resulted in substantial declines in the number of individuals starting treatment for TB in South Africa and risked progress toward achieving TB management goals. Exceptional effort will be needed to sustain gains in combating TB.