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Background: Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, in December 2019, it has spread rapidly, and many coronavirus disease (COVID-19) cases have occurred in Gwangju, South Korea. Viral mutations following the COVID-19 epidemic have increased interest in the characteristics of epidemics in this region, and pathogen genetic analysis is required for infection control and prevention., Methods: In this study, SARS-CoV-2 whole-genome analysis was performed on samples from patients with COVID-19 in Gwangju from 2020 to 2022 to identify the trends in COVID-19 prevalence and to analyze the phylogenetic relationships of dominant variants. B.41 and B.1.497 prevailed in 2020, the early stage of the COVID-19 outbreak; then, B.1.619.1 mainly occurred until June 2021. B.1.617.2, classified as sublineages AY.69 and AY.122, occurred continuously from July to December 2021. Since strict measures to strengthen national quarantine management had been implemented in South Korea until this time, the analysis of mutations was also able to infer the epidemiological relationship between infection transmission routes. Since the first identification of the Omicron variant in late December 2021, the spread of infection has been very rapid, and weekly whole-genome analysis of specimens has enabled us to monitor new Omicron sublineages occurring in Gwangju., Conclusions: Our study suggests that conducting regional surveillance in addition to nation-level genomic surveillance will enable more rapid and detailed variant surveillance, which will be helpful in the overall prevention and management of infectious diseases., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)