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There is a need to evaluate evolving trends in tuberculosis (TB) patient profiles, treatment outcomes and treatment success determinants, which this study assessed over a five-year period (2019–2023). We conducted a single site registry based study analysing TB patient data from 2019 to 2023, involving 1,051 tuberculosis patients who initiated treatment at Mildmay Uganda Hospital. Descriptive statistics summarized demographics and clinical characteristics, and annual cohort comparisons assessed changes over time. Treatment success was defined as cured or completed treatment. Chi-square, Fisher’s exact and logistic regression identified factors associated with treatment outcomes, with significance set at p < 0.05. Among 1,051 participants, most were male (55.2%), aged 34–50 years (40.8%), HIV-positive (72.1%), and residents of the Kampala Metropolitan Area (84.9%). Pulmonary TB was predominant, with 58.2% bacteriologically confirmed cases. Patient profiles included 91.0% new cases, 7.0% relapses, 0.6% failures, and 1.4% lost to follow-up. Relapse rose significantly from 0.7% in 2019 to 14.6% in 2023 (p < 0.001), while the proportion of new cases declined. Treatment outcomes also varied: cure rates improved steadily, reaching 65.7% in 2023, whereas treatment completion declined from 61.3% in 2019 to 22.6% in 2023. Mortality peaked at 10.2% in 2022, and treatment failure was highest in 2021 (2.7%).Unsuccessful outcomes were linked with, older age (≥ 50 years) (aOR = 3.66; 95% CI: 1.27–10.55; p = 0.016), being separated, divorced, or widowed (aOR = 1.86; 95% CI: 1.08–3.22; p = 0.027), and prior TB treatment failure (aOR = 18.45; 95% CI: 3.36–101.40; p = 0.001). This study demonstrates a shifting trend in TB patient profiles, with a notable increase in relapses over time. Unsuccessful treatment outcomes were associated with age ≥ 50 years, prior treatment failure, and being separated, divorced, or widowed. Strengthening post-treatment follow-up, adherence support is essential. Further prospective research on evolving TB patient profiles and treatment outcomes is critical to inform targeted interventions and optimize TB control strategies. Not applicable.