COVID -19 infections are a serious problem in the world, Africa, Ethiopia, and Amhara region. ABO blood types play a significant role in various illnesses like oncological, cardiovascular, and certain infectious and non-infectious diseases. Several types of research have been conducted to show the association between the human ABO and Rh blood group systems with COVID-19 infection susceptibility Therefore, this study was aimed to investigate the association of the ABO and Rh blood group systems with COVID-19 infection susceptibility from confirmed cases in referral hospitals of FHCSH and GURH in the Northwest Amhara Region, Ethiopia. A hospital based case-control study was conducted. Data analysis of demographic and clinical variables was performed using SPSS version 25. Of the 410 (206 males and 204 females) study subjects, 204 were found to be COVID-19 positive (104 males (50.98%) and 100(49.02%) female) and 206 were COVID-19 negative (102 males (49.5%) and 104(50.5%) female). Of the 204 COVID 19 positive cases, 174 (86 male (42.2%) and 88 female (43.14%) recovered from COVID-19 infection diseases, while 30 (18 (8.8%) male and 12 (5.1%) female) died as a result of COVID 19 infection. In Chi-square analysis, the human ABO blood groups were significantly associated with deceased and recovery (P = 0.009) groups. There was also a statistically significant association between the severity of illness and COVID-19 infection with the ABO blood group systems (P = 0.000). However, sex, age, infectious and non-infectious diseases, and COVID-19 symptoms were not significantly associated with the recovery and deceased groups. In multivariate analysis, the odds of COVID-19 infection susceptibility were five times (AOR: 6.531[95%CI, (1.374-31.031)], p=0.018 higher in the study subjects whose age range were found between 51 and 60 years. The blood groups AB were significantly associated with COVID 19 infection (AOR: 0.192[95%CI, (0.054-0.683)], (P=0.011) and subjects who had infectious diseases of pneumonia were two times more likely to have COVID-19 infection susceptibility than those of infectious diseases (AOR: 3.807[95%CI, (1.021–14.200)], p=0.047) was statistically significant.