Objectives: To evaluate the genomic diversity and geographic distribution of SARS-CoV-2 lineages in South America. Methods: SARS-CoV-2 lineages from a public dataset of 5583 South American genome assemblies were analyzed. Polymorphisms in the main open reading frames were identified and compared to those in the main lineages of epidemiological concern: B.1.1.7 (UK) and B.1.351 (South Africa). Results: Across 16 South American countries, 169 lineages were identified; major lineage B had the greatest diversity and broadest geographic distribution. Seventeen predominant lineages were analyzed revealing 2 dominant lineages of concern: P.1 (Brazilian variant) and B.1.1.7 with 94 and 28 genomes, respectively, both with 33 polymorphisms (other lineages displayed ≤24 polymorphisms). A high number of polymorphisms were detected with a limited number of common variable positions, in common with the profile of the main lineages of epidemiological concern. Conclusions: The ever-increasing genetic diversity of SARS-CoV-2 continues to lead to novel lineage emergence. Various variants and lineages are now present across South America, dominated by major lineage B. The circulation of P.1 and B.1.1.7 and the high number of polymorphisms highlight the importance of genomic surveillance to determine introduction events, identify transmission chains, trace emergence, and implement prevention, vaccination and control strategies.