COVID-19 infection is still a mystery in terms of its long-term effect on health and its consequences on hematological disorders. In this article, we are presenting two cases of pediatric B-lymphoblastic leukemia (B-ALL) with a previous history of COVID-19 infection. Notably, in both the cases the fluorescence-in situ hybridization (FISH) studies showed pathologic alteration of the RUNX1 gene. The finding of this genetic alteration along with known pre-leukemic translocation ETV6-RUNX1, opens a door for further exploration of the “second-hit” hypothesis regarding an infectious agent precipitating development of B-ALL in a genetically susceptible individual.