Background Polymorphisms in the interleukin-10 (IL10) gene have been linked to the severity of the patients infected with the viral infections. This study aimed to assess if the IL10 gene polymorphisms rs1800871, rs1800872, and rs1800896 were linked to coronavirus disease 19 (COVID-19) mortality in different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in the Iranian population. Methods For genotyping IL10 rs1800871, rs1800872, and rs1800896, this study used the polymerase chain reaction-restriction fragment length polymorphism method in 1,734 recovered and 1,450 deceased patients. Results The obtained finding indicated IL10 rs1800871 CC genotype in the Alpha variant and CT genotype in the Delta variant had a relationship with COVID-19 mortality; however, there was no association between rs1800871 polymorphism and the Omicron BA.5 variant. The COVID-19 mortality rate was associated with IL10 rs1800872 TT genotype in the Alpha and Omicron BA.5 variants and GT in the Alpha and Delta variants. The COVID-19 mortality rate was associated with IL10 rs1800896 GG and AG genotypes in the Delta and Omicron BA.5; nevertheless, there was no association between rs1800896 polymorphism with the Alpha variant. According to the obtained data, the GTA haplotype was the most common of haplotype in different SARS-CoV-2 variants. The TCG haplotype was related to COVID-19 mortality in the Alpha, Delta and Omicron BA.5 variants. Conclusion The IL10 polymorphisms had an impact on COVID-19 infection, and these polymorphisms had different effects in various SARS-CoV-2 variants. To verify the obtained results, further studies should be conducted on various ethnic groups.