According to the global burden of disease 5.5 million deaths were attributable to stroke. The stroke mortality rate is estimated to be seven times higher in low-income countries compared to high-income countries. The main aim of the study was to assess the 28 days case fatality rate and its determinants among admitted stroke patients in public referral hospitals, in Northwest Ethiopia. A hospital-based prospective cohort study was conducted from December 2020 to June 2021. The study population was 554 stroke patients. Based on Akakian Information Criteria, the Gompertz model was fitted to predict the hazard of death. The study included admitted stroke patients who were treated in the general medical ward and neurology ward. The mean age of the participants was 61 ± 12.85 years and 53.25% of the patients were female. The 28-days case fatality rate of stroke was 27.08%. The results from Gompertz parametric baseline hazard distribution revealed that female sex adjusted hazard rate (AHR = 0.27, 95% CI:0.18–0.42), absence of a family history of chronic disease (AHR = 0.50, 95%CI:0.29–0.87), good GCS score (AHR = 0.21, 95% CI:0.09–0.50) and the absence of complication during hospital admission (AHR = 0.16, 95% CI:0.08–0.29) were factors which decrease hazard of 28 days case fatality rate. While, hemorrhagic stroke sub-type (AHR = 1.38, 95% CI:1.04–3.19), time from symptom onset to hospital arrival (AHR = 1.49, 95% CI:1.57–2 .71), time from confirmation of the diagnosis to initiation of treatment (AHR = 1.03, 95% CI:1.01–1.04), a respiratory rate greater than 20 (AHR = 7.21, 95% CI:3.48–14.9), and increase in NIHSS score (AHR = 1.16, 95% CI:1.10–1.23) were factors increasing hazard of 28 days case fatality rate of stroke. At 28-days follow-up, more than one-fourth of the patients have died. The establishment of separate stroke centers and a network of local and regional stroke centers with expertise in early stroke evaluation and management may address challenges.