Reliable real-world data on direct acting anti-retroviral (DAA) uptake and treatment outcomes are lacking for patients with hepatitis C virus (HCV) in sub-Saharan Africa. This study provides data on HCV DAA-based treatment outcomes, mortality, loss-to-follow up, and associated factors among patients in Eritrea. A multicenter retrospective observational cohort study was conducted in two tertiary hospitals in Asmara, Eritrea. A structured checklist was used to collect data from patient’s cards. Descriptive and inferential statistics used included means (± Standard deviation (SD), medians (Interquartile range (IQR), chi-squire (χ2), Kaplan–Meier estimates, and multivariate Cox proportional hazard models. A total of 238 patients with median age of 59 years (IQR 50–69 years) were enrolled in the study. Out of the 227 patients initiated on treatment, 125 patients had viral load measurements at 12 weeks after end of treatment (EOT) whereas 102 patients had no viral load measurements at 12 weeks EOT. Among the patients with HCV RNA data post-EOT 12, 116 (92.8%) had sustained viral response (SVR). The prevalence of death and loss-to-follow up (LTFU) were (7.5%, 95% CI 1.7–4.1) and 67 (28.1%, 95% CI 22.3–33.9) translating into an incidence of 1.1 (95% CI 0.8–1.5) per 10,000 person days. Independent predictors of LTFU included the enrollment year (2020: aHR = 2.2, 95% CI 1–4.7; p value = 0.04); Hospital (Hospital B: aHR = 2.2, 95% CI 1–4.7; p value = 0.03) and the FIB-4 score (FIB-Score < 1.45: aHR = 3.7, 95% CI 1.2–11.5; p value = 0.02). The SVR rates achieved in this cohort were high. However, high LTFU and high mortality driven largely by late presentation and suboptimal population screening/case finding, were uncovered. These challenges can be addressed by test-and-treat programs that simultaneously prioritize programmatic screening, decentralization of care, and better patient tracking in the HCV care cascade.