The pandemic of coronavirus disease 2019 (COVID-19) is caused by a novel member of the family Coronaviridae, now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent studies revealed the emergence of virus variants with substitutions in the spike and/or nucleocapsid and RNA-dependent RNA polymerase proteins that are partly responsible for enhanced transmission and reduced or escaped anti-SARS-CoV-2 antibodies that may reduce the efficacy of antibodies and vaccines against the first identified SARS-CoV-2 strains. In order to gain insight into the emergence and evolution of SARS-CoV-2 variants circulating in the South American region, a comprehensive phylogenetic study of SARS-CoV-2 variants circulating in this region was performed. The results of these studies revealed sharp increase in virus effective population size from March to April of 2020. At least 62 different genotypes were found to circulate in this region. Variants of concern (VOCs) Alpha, Beta, Gamma and Delta co-circulate in the region, together with variants of interest (VOIs) Lambda, Mu and Zeta. Most of SARS-CoV-2 variants circulating in the South American region belongs to B.1 genotypes and have substitutions in the spike and/or nucleocapsid and polymerase proteins that confer high transmissibility and/or immune resistance. 148 amino acid positions of the spike protein and 70 positions of the nucleocapsid were found to have substitutions in different variants isolated in the region by comparison with reference strain Wuhan-Hu-1. Significant differences in codon usage among spike genes of SARS-CoV-2 strains circulating in South America was found, which can be linked to SARS-CoV-2 genotypes.