Background: Coronavirus Disease of 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients had varying clinical symptoms and disease severity (mild, moderate, severe, and critical). Several risk factors, including genetic polymorphisms, have been reported to be associated with disease risk and severity. This study aimed to investigate the association of two polymorphisms in the orosomucoid1-like 3 (ORMDL3) and a disintegrin and metalloprotease 33 (ADAM33) asthma-related genes with the severity of COVID-19. Material and methods: The study included 116 COVID-19 patients with a positive polymerase chain reaction (PCR) test for the SARS-CoV-2 Delta variant. 58 patients with moderate symptoms, 28 patients with severe symptoms, and 30 outpatients with mild symptoms. Genotyping of rs7216389 in the ORMDL3 and rs2280091 in ADAM33 genes was performed by polymerase chain reaction-restriction fragment length polymorphism. Furthermore, records of patients were studied for hematological profiles and biochemical markers. Results: No significant association was found between rs7216389 and rs2280091 and the severity of COVID-19 between different groups of COVID-19 patients. The serum levels of RBC and neutrophil-to-lymphocyte ratio were significantly increased; the erythrocyte sedimentation rate (ESR), and Aspartate transaminase (SGOT) were significantly decreased during treatment in intensive care unit (ICU) patients. The serum levels of red blood cells, Platelets, Urea, Alkaline phosphatase, ESR, Alanine transaminase (SGPT), and SGOT were significantly increased during treatment in hospitalized patients. The serum levels of inflammatory factors, including C-reactive protein (CRP), D-dimer, and Ferritin at the time of admission, were significantly higher in patients admitted to the ICU patients compared to the other group of patients. Conclusion: The two polymorphisms studied in this research are not suitable markers for predicting the severity of COVID-19. However, there are significant differences in the amounts of some blood factors in different groups of COVID-19 patients (P < 0.05) and these factors can be used as a marker for the disease severity prediction.