Background Eritrea has achieved the global target (90%) for tuberculosis (TB) treatment success rate. Though, events of unsuccessful TB treatment outcomes (death, treatment failure, lost to follow up and not evaluated) could lead to further TB transmission and the development of resistant strains. Hence, factors related to these events should be explored and addressed. This study aims to fill the gap in evidence by identifying the determinants of unsuccessful TB treatment outcomes in Eritrea’s Northern Red Sea region. Methods A retrospective cohort study was conducted in Eritrea’s Northern Red Sea region. Data collected using a data extraction tool was analyzed using Stata version 13. Frequencies, proportions, median and standard deviations were used to describe the data. Furthermore, univariable and multivariable logistic regression analysis were performed to determine the risk factors for unsuccessful TB treatment outcomes. Crude odds ratio (COR) and adjusted odds ratio (AOR) with their 95% confidence interval (CI) presented and p-value < 0.05 was considered statistically significant. Results Among 1227 TB patients included in this study, 9.6% had unsuccessful TB treatment outcomes. In multivariable logistic regression analysis, TB cases 55–64 years old (AOR: 2.75[CI: 1.21–6.32], p = 0.016) and those ≥ 65 years old (AOR: 4.02[CI: 1.72–9.45], p = 0.001) had 2.7 and 4 times higher likelihood of unsuccessful TB treatment outcome respectively. In addition, HIV positive TB patients (AOR: 5.13[CI: 1.87–14.06], p = 0.002) were 5 times more likely to have unsuccessful TB treatment outcome. TB treatment in Ghindae Regional Referral Hospital (AOR: 5.01[2.61–9.61], p < 0.001), Massawa Hospital (AOR: 4.35[2.28–8.30], p< 0.001) and Nakfa Hospital (AOR: 2.53[1.15–5.53], p = 0.021) was associated with 5, 4 and 2.5 higher odds of unsuccessful TB treatment outcome respectively. Conclusion In this setting, old age, HIV co-infection and health facility were the independent predictors of unsuccessful TB treatment outcome.