BACKGROUND: Despite the effectiveness of antiretroviral therapy in reducing mortality from opportunistic infections among people living with HIV (PLHIV), tuberculosis (TB) continues to be a significant cause of death, accounting for over one-third of all deaths in this population. In Ethiopia, there is a lack of comprehensive and aggregated data on the national level for TB-associated mortality during co-infection with HIV. Therefore, this systematic review and meta-analysis aimed to estimate TB-associated mortality and identify risk factors for PLHIV in Ethiopia. METHODS: We conducted an extensive systematic review of the literature using the Preferred Reporting of Systematic Review and Meta-Analysis (PRISMA) guidelines. More than seven international electronic databases were used to extract 1,196 published articles from Scopus, PubMed, MEDLINE, Web of Science, HINARY, Google Scholar, African Journal Online, and manual searching. The pooled mortality proportion of active TB was estimated using a weighted inverse variance random-effects meta-regression using STATA version-17. The heterogeneity of the articles was evaluated using Cochran's Q test and statistic test. Subgroup analysis, sensitivity analysis, and Egger's regression were conducted to investigate publication bias. This systematic review is registered in Prospero with specific No. CRD42024509131. RESULTS: Overall, 22 individual studies were included in the final meta-analysis reports. During the review, a total of 9,856 cases of TB and HIV co-infection were screened and 1,296 deaths were reported. In the final meta-analysis, the pooled TB-associated mortality for PLHIV in Ethiopia was found to be 16.2% (95% CI: 13.0-19.2, = 92.9%, = 0.001). The subgroup analysis revealed that the Amhara region had a higher proportion of TB-associated mortality, which was reported to be 21.1% (95% CI: 18.1-28.0, = 84.4%, = 0.001), compared to studies conducted in Harari and Addis Ababa regions, which had the proportions of 10% (95% CI: 6-13.1%, = 83.38%, = 0.001) and 8% (95% CI: 1.1-15, = 87.6%, = 0.001), respectively. During the random-effects meta-regression, factors associated with co-infection of mortality in TB and HIV were identified, including WHO clinical stages III & IV (OR = 3.01, 95% CI: 1.9-4.7), missed co-trimoxazole preventive therapy (CPT) (OR = 1.89, 95% CI: 1.05-3.4), and missed isoniazid preventive therapy (IPT) (OR = 1.8, 95% CI: 1.46-2.3). CONCLUSION: In Ethiopia, the mortality rate among individuals co-infected with TB/HIV is notably high, with nearly one-fifth (16%) of individuals succumbing during co-infection; this rate is considered to be higher compared to other African countries. Risk factors for death during co-infection were identified; the included studies examined advanced WHO clinical stages IV and III, hemoglobin levels (≤10 mg/dL), missed isoniazid preventive therapy (IPT), and missed cotrimoxazole preventive therapy (CPT) as predictors. To reduce premature deaths, healthcare providers must prioritize active TB screening, ensure timely diagnosis, and provide nutritional counseling in each consecutive visit. SYSTEMATIC REVIEW REGISTRATION: Trial registration number in Prospero =CRD42024509131 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=509131.