ObjectivesThe study determined tuberculosis (TB) treatment outcomes in Southern Ghana from 2012 to 2021. MethodsA retrospective analysis of service data on TB cases was conducted. Treatment success was defined as TB cure or completion of treatment course, whereas unsuccessful outcomes was defined as death, failure of treatment and lost to follow up. Bivariate and multivariate logistic regression was used to determine factors associated with treatment outcomes. ResultsA total of 4106 adult TB cases were reported with a median age of 41 (interquartile range 32-52) years. Of these, 93.1% (n = 3823) were newly diagnosed. The treatment success rate declined from 71.0% in 2012 to 55.7% in 2021 (ktau-b = −0.56, P = 0.0318). Clinically diagnosed TB and extra-pulmonary TB had 7.0% (adjusted prevalence ratio [aPR]: 0.93, 95% confidence interval [CI]: 0.88-1.00) and 24.0% (aPR: 0.76, 95% CI: 0.69-0.84) respectively, less successful treatment outcome compared to pulmonary TB patients. HIV negative status was associated with 22% higher successful treatment outcome compared with being HIV positive (aPR: 1.22, 95% CI: 1.12-1.33). ConclusionTuberculosis treatment success rate declined over the period. There is a need for the TB Control Programme to review the national and sub-national TB data to ascertain poor performing TB treatment sites to identify and address context specific challenges with treatment interventions and system inadequacies to improve treatment success rates.