BackgroundTuberculosis (TB) is among the leading causes of death globally. The disease has a huge burden in Namibia, with a case notification rate of at least 442 per 100,000. To date, Namibia is among the countries with the highest global TB burden, despite all efforts to reduce it. This study aimed to determine the factors associated with the unsuccessful treatment outcomes of the Directly Observed Therapy Short course (DOTS) programme in the Kunene and Oshana regions.MethodsThe study utilised a mixed-methods explanatory-sequential design to collect data from all TB patient records and healthcare workers who work directly with the DOTS strategy for TB patients. The relationship between independent and dependent variables was analysed using multiple logistic regression analysis, while interviews were analysed using inductive thematic analysis.ResultsThe overall treatment success rates of the Kunene and Oshana regions throughout the review period were 50.6% and 49.4%, respectively. The logistic regression analyses showed that in the Kunene region, the type of DOT used (Community-based DOTS) (aOR = 0.356, 95% CI: 0.835–2.768,p= 0.006) was statistically significant with the unsuccessful treatment outcomes. While in the Oshana region, age groups 21–30 years old (aOR = 1.643, 95% CI = 1.005–2.686,p= 0.048), 31–40 years old (aOR = 1.725, 95% CI = 11.026–2.9,p= 0.040), 41–50 years old (aOR = 2.003, 95% CI = 1.155–3.476,p= 0.013) and 51–60 years old (aOR = 2.106, 95% CI = 1.228–3.612,p= 0.007) had statistically significant associations with the poor TB-TO. Inductive thematic analysis revealed that patients in the Kunene region were challenging to reach owing to their nomadic lifestyle and the vastness of the area, adversely affecting their ability to observe TB therapy directly. In the Oshana region, it was found that stigma and poor TB awareness among adult patients, as well as mixing anti-TB medication with alcohol and tobacco products among adult patients, was a prevalent issue affecting TB therapy.ConclusionThe study recommends that regional health directorates embark on rigorous community health education about TB treatment and risk factors and establish a robust patient observation and monitoring system to enhance inclusive access to all health services and ensure treatment adherence.