Objectives: This study examined the correlation between the ABO blood group system, Rh factors, and the susceptibility and severity of COVID-19. It also analyzed blood parameters and their association with disease outcomes . Materials & Methods: A total of 286 nasopharyngeal swabs were collected following WHO guidelines for SARS-CoV-2 RNA detection. RNA was extracted using three kits: QIAamp, Viral RNA (QIAGEN), and the Mini kit. Reverse transcription polymerase chain reaction (RT-PCR) confirmed positive cases, and the Phoenix Dx 2019-nCoV kit was used for real-time PCR. Results: Of the 286 patients, 153 (53.50%) were female, and 133 (46.50%) were male. COVID-19 was more common in females across all ABO blood groups (A: 52.4%, AB: 52%, B: 50%, O: 59.7%), with blood group A being the most prevalent. Severe cases were mostly blood group A (45.6%), while group O accounted for only 0.68%. In moderate cases, blood group B was predominant (44.7%). Rh-positive individuals were more prone to severe infection. Patients with severe disease showed lower hematological parameters, including hemoglobin, lymphocytes, white blood cells, red blood cells, and platelets, while moderate cases had higher white blood cell counts. Lymphopenia was prevalent in all COVID-19 patients. Conclusion: This study highlights the relationship between ABO blood groups and COVID-19 severity, identifying comorbidities as significant contributors to mortality, particularly in Ghadamis City, Libya. Furthermore, the study provides an overview of the health status of COVID-19 patients in our region.