Acute coronary syndrome (ACS) is increasingly becoming a common cause of cardiovascular mortality in developing countries. Even though, there is an introduction of limited percutaneous coronary intervention and thrombolytic therapies, in-hospital mortality due to ACS still remains high in sub-Saharan countries. The aim of the study was to assess treatment outcome of ACS patients admitted to Ayder Comprehensive Specialized Hospital, Mekelle, Ethiopia. A retrospective cross-sectional study was done by collecting data from patients' medical records using a data abstraction tool. Data were analyzed using logistic regression to determine crude and adjusted odds ratio. At 95% confidence interval, p-value<0.05 was considered as statistically significant. Of the total 151 patients, in-hospital mortality was found to be 24.5%, and hypertension was the most frequent (46.4%) risk factor of ACS. Concerning the management practice, catheterization and primary percutaneous coronary intervention were done in 27.1%, and 3.9% respectively. Additionally, in emergency setting loading dose of aspirin and clopidogrel were used in about 63.8% and 62.8%, respectively. The other frequently used medications were beta-blockers (86.9%), angiotensin converting enzymes/angiotensin receptor blockers (84.1%) and statins (84.1%). Streptokinase was administered in 6.3% of patients with ST-elevated myocardial infarction and heparins in 78.1% of them. The commonly prescribed discharge medications were aspirin (98.2%), statins (94.7%) and clopidogrel (92%). Non-use of beta-blockers (p = 0.014), in-hospital complication of cardiogenic shock (p = 0.001) and left ventricular ejection fraction of ≤ 30% (p = 0.032) were independent predictors of in-hospital mortality. The proportion of in-hospital mortality due to ACS was found to be high. Therefore, timely evidence based therapy should be implemented in the setup.