South America, once an epicenter of COVID-19, has stayed on the road of continued management of the pandemic. The region initially struggled to cope with the pandemic as it experienced spiraling numbers of infections and overwhelmed public health systems. South America has risen in its pandemic response to be the region with the highest global vaccination rate. The region posed a strong vaccination drive, with over 76% of its population fully vaccinated with the initial protocol. South America leveraged its deeply rooted vaccination culture and public health confidence among its population. Herd immunity is an integral concept in population infectious disease management. Attaining herd immunity is presently not feasible with available vaccines, but the high vaccination rate in the region depicts the acceptance of vaccination as a strategy for population protection. The availability of effective transmission-blocking vaccines, the continuous implementation of strategies that will enable the undisrupted supply of the vaccines, equity in access to the vaccines, improved vaccine acceptance, and trust in the vaccination and public health systems will help shepherd the region towards herd immunity. Local vaccine production backed with investment in infrastructure and international collaboration for research and knowledge development will also drive population safety.