The Major Histocompatibility Complex (MHC) plays a key role in immune defense by binding pathogenic peptides and presenting them to T cells, which coordinate the host’s immune response. MHC is both polygenic and polymorphic, making it a crucial genomic region in pathogen recognition and immune adaptation. Among the class I genes, Human Leukocyte Antigen-A (HLA-A), HLA-B, and HLA-C are the most frequently analyzed. HLA typing has advanced from serological methods to next-generation sequencing (NGS), which improves accuracy, throughput, and read length. However, challenges remain, such as incomplete reference genomes due to the complexity of the HLA region. MHC is strongly associated with infectious and autoimmune diseases, as well as pharmacogenetics. This study investigated SNPs in HLA-A, HLA-B, and HLA-C in 60 COVID-19 patients with mild, moderate, and severe symptoms using NGS. The results were compared to the Single Nucleotide Polymorphism database (dbSNP), and statistical analysis revealed several SNPs with significant differences across symptom severity groups. Notably, SNPs rs2308527, rs1071817, rs1050518, and rs1065386 showed statistically significant associations and have been previously linked to hepatocellular carcinoma, moyamoya disease, cervical carcinoma, and diabetic retinopathy, respectively. These findings highlight the potential role of HLA variants in influencing COVID-19 outcomes.