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Abstract Background The COVID-19 pandemic has been the most significant health challenge of the last century. Multiple and successive waves of COVID-19 cases, driven particularly by the emergence of new SARS-CoV-2 variants, have kept the world in a constant state of alert. Methods We present an observational, descriptive, cross-sectional study aimed at identifying SARS-CoV-2 variants circulating during two local waves of COVID-19 cases in southern Bahia, Brazil (late 2021 and late 2022), and analyzing the association between the detected variants and the epidemiological and clinical characteristics of the disease. For this purpose, data and nasopharyngeal samples from individuals in southern Bahia, Brazil, with suspected COVID-19 were included. Viral detection was performed by RT-qPCR, and SARS-CoV-2 variants were identified by next-generation viral sequencing. Results A total of 368 nasopharyngeal samples were tested. Approximately 23% of the samples from late 2021 tested positive for SARS-CoV-2, while in 2022, the positivity rate was about 56%. All sequenced samples from 2021 were identified as the Delta variant, while in 2022, all samples were classified as the Omicron variant. Overall, individuals who tested positive for SARS-CoV-2 in 2022 were younger than those who tested positive in 2021. Moreover, we observed significant differences in the clinical spectrum of SARS-CoV-2 infection when comparing the two periods. Individuals who presented with anosmia/ageusia were more likely to test positive for SARS-CoV-2 infection in 2021 but not in 2022. Additionally, fever, dry cough, pharyngalgia, headache, and rhinorrhea were more frequent among individuals infected with the Omicron variant than among those infected with the Delta variant. Conclusions The profile of COVID-19 in southern Bahia differed when analyzing two distinct waves of the pandemic in the region. These differences are likely related to the variants, which may differ in transmissibility and virulence, thereby altering the dynamics of the pandemic. This underscores the importance of genomic surveillance in better understanding the behavior of viral infections.