Although awareness of the Zika virus has existed since the 1950s, only recently has it attracted the interest of the international community. In 2015 and 2016, the virus spread throughout Brazil and suspicions on the possible relation between parallel increases in neurological disorders and the infection arose. By November 2015, this concern had developed into a National Public Health Emergency. On February 1, 2016, WHO formally declared its suspicion that this was a Public Health Emergency of International Concern (PHEIC), and sent a response in accordance with International Health Regulations (2005). Zika is present in almost all South American countries, and PAHO/WHO, Unasur, and Mercosur are developing responsive actions to the epidemic. The aim of this article is to present a critical analysis of the regional South American and Brazilian responses of February through September 2016, in respect of this PHEIC announcement, utilizing qualitative methodologies via bibliographical examination and document analysis. In this context, the PAHO/WHO played a prominent role as compared with the other organizations. Moreover, the political environment of the region also played a major role in the instability of both Mercosur and Unasur, which could impact the capacity and effectiveness of the response.