We conducted a qualitative exploration into the palatability and acceptability of a novel fixed-dose combination (FDC) anti-tuberculosis drug. This study was nested in the SHINE (Shorter treatment for minimal TB in children) trial, which compares the safety and efficacy of treating non-severe drug-susceptible tuberculosis (TB) with a 6 vs. 4 months anti-tuberculosis regimen in children aged 0-16 years. Participants were recruited in Cape Town, South Africa. To describe the palatability and acceptability of a FDC of rifampicin, isoniazid and pyrazinamide among South African children and their caregivers in the SHINE trial. We conducted 20 clinic observations of treatment administration, during which we conducted 16 semi-structured interviews with children and their caregivers. Data were organised thematically to report on experiences with administering and ingesting the FDC. Children and caregivers' experiences varied from delight to disgust. In general, participants said that the FDC compared favourably to other formulations. Pragmatic challenges such as dissolving the FDC and the time required to administer the FDC impeded caregivers' ability to integrate treatment into their daily routines. Drug manipulation was common among caregivers to improve TB treatment administration. This novel FDC appears acceptable for children, albeit with practical challenges to administration. Scale-up of FDC use should include supplementary intervention components to support caregivers.