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The COVID-19 epidemic in the Amazonas state, Brazil, during 2021 was driven by the spread of the Variant of Concern (VOC) Gamma (lineage P. 1) and, more recently, of the Gamma plus variants harboring deletions in the N-terminal (NTD) domain (lineage P. 1.3) or mutations at the S1/S2 junction (lineages P. 1.4 to P. 1.6) of the Spike protein. Here, we describe the analysis of 1,132 SARS-CoV-2 whole-genome sequences from individuals diagnosed in the Amazonas state from 1st July to 15th October 2021, representing 4.5% of all confirmed cases in the state in this period. Our genomic survey reveals a sharp reduction in the prevalence of VOCs Gamma and Gamma plus and the increase in the relative prevalence of the VOC Delta from 1% of SARS-CoV-2 samples sequenced in July to 89% of samples in October 2021. During this period, we also detected the introduction of the variant of interest (VOI) Mu, which remained in a low prevalence (< 1%) in August and September 2021. These findings revealed that the VOC Delta outcompeted variants Gamma, Gamma plus, and Mu even in the Amazonas State, a setting with one of the world’s highest hybrid (natural and vaccine) immunity thresholds. Notably, while the VOC Delta progressively replaced the other variants between July and October 2021, the total number of SARS-CoV-2 cases decreased in Amazonas.