This study describes the emergence and rapid spread of a new SARS-CoV-2 lineage (designated 501YV2 or B.1.351) in South Africa. The lineage, characterized by eight mutations in the spike protein, including three substitutions (K417N, E454K, and N501Y) in the receptor-binding domain, was identified after the first wave of the epidemic in Nelson Mandela Bay, Eastern Cape. It spread rapidly and became dominant in Eastern Cape, Western Cape, and KwaZulu-Natal provinces within weeks. Genomic data suggest that this lineage may have a selective advantage, possibly due to increased transmissibility or immune escape. The study highlights the importance of coordinated molecular surveillance to detect and characterize new lineages and inform global responses to the pandemic.This study describes the emergence and rapid spread of a new SARS-CoV-2 lineage (designated 501YV2 or B.1.351) in South Africa. The lineage, characterized by eight mutations in the spike protein, including three substitutions (K417N, E454K, and N501Y) in the receptor-binding domain, was identified after the first wave of the epidemic in Nelson Mandela Bay, Eastern Cape. It spread rapidly and became dominant in Eastern Cape, Western Cape, and KwaZulu-Natal provinces within weeks. Genomic data suggest that this lineage may have a selective advantage, possibly due to increased transmissibility or immune escape. The study highlights the importance of coordinated molecular surveillance to detect and characterize new lineages and inform global responses to the pandemic.