Coronavirus disease 2019 (COVID-19) is a pandemic with a multitude of manifestations and associations with the ABO blood group. Our study foucous the significant association of blood groups with the severity of COVID-19 disease and mortality. It was a retrospective study of patients with COVID-19 in Al Medina . Blood groups A, B, O, and AB were identified in every participant, irrespective of their RH type, and allotted groups 1, 2,3, and 4, respectively. Correlation between blood group and lab parameters was presented as histogram distributed among the four groups. Multivariate correlation and logistic regression were used for inferential statistics. The cohort included 350 patients: 136 (38.86%) participants had blood group O as the prevalent blood type. Overall, 10.21% COVID-19-related mortality was observed at our center. Mortality was 3.42% in blood group A, 2.28% in group B, 3.71% in group O, and 0.28% in AB blood group (P= <0.0001). Regarding the severity of COVID-19 disease, there was a statistical difference seen between the blood groups. In conclusion, this investigation showed a significant association of blood groups with the severity of COVID-19 disease and COVID-19 associated mortality.