Background: Understanding determinants of developing severe COVID-19 disease is important as studies show that severe disease is associated with worse outcomes. Objective: The study aimed to assess the determinants of COVID-19 disease severity among COVID-19 patients admitted to Millennium COVID-19 Care Center in Ethiopia. Methods: A cross-sectional study was conducted from June to August 2020 among randomly selected 686 patients. Chi-square test was used to detect the presence of a statistically significant difference in the characteristics of the patients based on disease severity (Mild Vs Moderate Vs Severe), where p-value of <0.05 was considered as having a statistically significant difference. A Multivariable multinomial logistic regression model was used to assess the presence of a significant association between the independent variables and COVID-19 disease severity where Adjusted Odds ratio (AOR), 95% CIs for AOR and P-values were used for testing significance and interpretation of results. Results: Having moderate as compared with mild disease was significantly associated with having hypertension (AOR= 2.302, 95% CI= 1.266, 4.184, p-value=0.006), diabetes mellitus (AOR=2.607, 95% CI= 1.307, 5.198, p-value=0.007 for diabetes mellitus), fever (AOR= 6.115, 95% CI= 2.941, 12.716, p-value=0.0001) and headache (AOR= 2.695, 95% CI= 1.392, 5.215, p-value=0.003). Similarly, having severe disease as compared with mild disease was associated with age group (AOR= 4.428, 95% CI= 2.497, 7.853, p-value=0.0001 for 40-59 years and AOR=18.070, 95% CI=9.292, 35.140, p-value=0.0001 for ≥ 60 years), sex (AOR=1.842, 95% CI=1.121, 3.027, p-value=0.016), hypertension (AOR= 1.966, 95% CI= 1.076, 3.593, p-value=0.028), diabetes mellitus (AOR= 3.926, 95% CI= 1.964, 7.847, p-value=0.0001), fever (AOR= 13.218, 95% CI= 6.109, 28.601, p-value=0.0001) and headache (AOR= 4.816, 95% CI= 2.324, 9.979, p-value=0.0001). In addition, determinants of severe disease as compared with moderate disease were found to be age group (AOR= 4.871, 95% CI= 2.854, 8.315, p-value=0.0001 for 40-59 years and AOR= 18.906, 95% CI= 9.838, 36.334, p-value=0.0001 for ≥ 60 years), fever (AOR= 2.161, 95% CI= 1.286, 3.634, p-value=0.004) and headache (AOR= 1.787, 95% CI= 1.028, 3.107, p-value=0.039). Conclusions: Being old, male sex, hypertension, diabetes mellitus, and having symptoms of fever and headache were found to be determinants of developing a more severe COVID-19 disease category. We recommend a better preventive practice to be set in place so that these groups of patients can be protected from acquiring the disease. And for those who are already infected, a more careful follow-up and management should be given so that complication and death can be prevented. Furthermore, considering the above non respiratory symptoms as disease severity indicator could be important.