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Background Coronavirus disease 2019 (COVID-19) is a devastating pandemic-causing disease with a variable severity among populations. Genetic studies have pinpointed angiotensin-converting enzyme 2 (ACE2), a key enzyme for viral entry, for its possible linkage to the disease progression. The present study aimed to investigate the potential association between single nucleotide polymorphisms (SNPs) of human ACE2 gene with the severity and outcomes of COVID-19 for better patient management. Methods In this observational cross-sectional study, COVID-19 confirmed patients were classified into moderate and severe cases according to the “Ain Shams University Hospitals Pocket Guide for COVID-19 Diagnosis.” Genetic analysis of ACE2 SNP rs2048683 was carried out using a TaqMan assay with the real-time polymerase chain reaction (PCR) technique. Results Among 90 confirmed COVID-19 patients, 78.9% (71/90) were classified as severe, and 21.1% (19/90) were classified as moderate. Laboratory biomarkers were significantly (P = 0.000) higher in the severe group than in the moderate group. Similarly, associated comorbidities such as hypertension were significant (P = 0.000) in the severe group, whereas asthma and deep venous thrombosis were significant in the moderate group (P = 0.007 and 0.006, respectively). Elevated serum ferritin level (odds ratio (OR) 162.589, 95% confidence interval (CI) 8.108–3260.293) and ACE2 rs2048683 genotype GG/G (OR 5.852, 95% CI 1.586–21.591) were both considered independent risk factors for severe disease. Conclusion The findings of the present study provide preliminary evidence of an association between ACE2 rs2048683 SNPs and COVID-19 severity in the Egyptian population, which may inform the need for targeted management.