ABSTRACT The disease burden of Streptococcus pyogenes is particularly high in low- and middle-income countries. However, data on the molecular epidemiology of S. pyogenes in such regions, especially sub-Saharan Africa, are scarce. To address this, whole-genome sequencing (WGS) of S. pyogenes from Gabon was performed to identify transmission clusters and provide valuable genomic data for public repositories. A total of 76 S . pyogenes isolates from 73 patients, collected between September 2012 and January 2013, were characterized by short-read whole-genome sequencing. The predominant emm types were emm 58.0, emm 81.2 and emm 223.0 with 9.2% (7 of 76), 7.9% (6 of 76), and 6.6% (5 of 76), respectively. Single-nucleotide polymorphism analysis revealed 16 putative transmission clusters. Four of these were household transmissions. Four antimicrobial genes ( lmrP , tetM , tetL , and thfT ) were found in the S. pyogenes isolates from this study. All strains carried lmrP . Of the 76 isolates, 64 (84.2%) carried at least one tetracycline resistance gene ( tetM or tetL ). Comparisons with other publicly available African genomic data revealed a significant correlation between geographical location and genetic diversity of S. pyogenes , with Gabonese strains showing similarities to those from Kenya and certain Oceanian regions. Our study showed that transmission of S. pyogenes can occur at the community/household level and that high-resolution molecular typing is needed to monitor changes in circulating clones and to detect community outbreaks. Advocacy for the adoption of WGS for comprehensive molecular characterization of S. pyogenes and data sharing through public repositories should be encouraged to understand the molecular epidemiology and evolutionary trajectory of S. pyogenes in sub-Saharan Africa. IMPORTANCE The study conducted in Gabon underscores the critical importance of addressing the limited knowledge of the molecular epidemiology of Streptococcus pyogenes in low- and middle-income countries, particularly sub-Saharan Africa. Our molecular analysis identified predominant emm types and unveiled 16 putative transmission clusters, four involving household transmissions. Furthermore, the study revealed a correlation between geographical location and genetic diversity, emphasizing the necessity for a comprehensive understanding of the molecular epidemiology and evolutionary trajectory of S. pyogenes in various regions. The call for advocacy in adopting whole-genome sequencing for molecular characterization and data sharing through public repositories is crucial for advancing our knowledge and implementing effective strategies to combat the spread of S. pyogenes in sub-Saharan Africa.