For more than 70 years, the countries of South America have been attempting to eliminate foot-and-mouth disease (FMD), but a regional strategy had not been established by all the affected countries until 1988. The Action Plan 1988–2009 of the Hemispheric Program for the Eradication of Foot-and-Mouth Disease (PHEFA 1988–2009) resulted in an FMD-free status in 88.4% of the bovine population of South America. However, countries of the Andean sub-region maintained an FMD endemic. In addition, sporadic outbreaks in vaccinated cattle populations have been reported in countries of the Southern Cone, endangering the disease-free status in these countries. Within this context, the PHEFA 2011–2020 was approved to eliminate FMD from the subcontinent, and this review describes the most important milestones during its execution. FMD in Ecuador and sporadic outbreaks in the Southern Cone sub-region were effectively eliminated. The outbreaks that occurred in Colombia in 2017 and 2018 were successfully controlled. The type C virus was removed from the vaccines in use in most countries, based on a risk assessment. This review also describes the progress made by the countries advancing toward official recognition as FMD-free in all their territories, with Bolivia, Brazil, and Peru leading the progressive suspension of vaccination to achieve FMD-free status without vaccination. Consequently, at the end of PHEFA 2011–2020, Venezuela was, and still is, the only country in the region whose control program has suffered setbacks, and no evidence has suggested that the transmission and infection of the bovine population have been eliminated. At the end of 2020, a new PHEFA Action Plan 2021–2025 was approved with a five-year horizon, to complete the eradication of the disease in the Americas.