An essential metric for determining the efficacy of tuberculosis (TB) control programs is the evaluation of TB treatment outcomes; this study was conducted to investigate treatment outcomes and associated factors among tuberculosis patients in rural areas of Eastern Cape, South Africa. Assessing treatment outcomes is fundamental to facilitating the End TB Strategy’s set target. Clinic records from 457 patients with DR-TB were examined for data collection while 101 patients were followed up prospectively. Data were analyzed using Stata version 17.0. The odds ratio and 95% confidence interval were calculated to check the association between variables.p≤ 0.05 was considered statistically significant. Of the 427 participants, 65.8% had successful treatment whilst 34.2% had unsuccessful TB treatment. A total of 61.2% and 39% of the HIV-positive and HIV-negative participants had a successful TB treatment whilst 66% and 34% of both HIV-negative and positive participants had unsuccessful TB treatment. From the 101 patients that were followed up, smokers took longer to have treatment outcomes compared to non-smokers. In the study with HIV/TB co-infection, men predominated. HIV and tuberculosis co-infection made therapy difficult with unfavorable effects on TB management. The treatment success rate (65.8%) was lower than the WHO threshold standard with a high proportion of patients being lost to the follow up. The co-infection of tuberculosis and HIV resulted in undesirable treatment outcomes. Strengthening TB surveillance and control is recommended.