Trisomy 21 (Down syndrome) is a chromosomal disorder associated with humoral and cellular immunologic impairments among other systemic manifestations. It occurs at a frequency of 1 in 750 live births. There are increasing reports of children with Down syndrome presenting signs of severe COVID-19. The literature from Africa on pediatric COVID-19 and risk stratification for severe disease is scant. A summary of the clinical features, complications, and treatment outcomes of three Ethiopian children with Trisomy 21 and severe COVID-19 along with a discussion of the correlation between trisomy 21 immunology and severe SARS CoV-2 infection is presented.