During the 2022 monkeypox (mpox) epidemic’s first 100 days, 99 non-endemic countries, including 25 Latin American and Caribbean (LAC) countries, reported >64,000 cases. We aim to assess the cases’ introduction, epidemiological profile, initial response, transmission dynamics, and main challenges ahead among LAC countries during the first 100 days of the mpox 2022 epidemic. We used mixed methods, including desktop research and open data analysis. The 2022 mpox epidemic has progressed consistently through LAC, with Brazil and Peru combining for over 80% of the confirmed LAC cases. Although Brazil reports the highest mpox case counts (n = 4472), Peru reports the highest incidence (41 confirmed cases per 1 million inhabitants). Initially, LAC missed the opportunity to focus on the high-risk population, including the people living with HIV (PLHIV) and gay, bisexual, and men who have sex with men (GBMSM). Moreover, the main challenges ahead include stigmatization, vaccine inequity, barriers to accessing diagnostics, and complete isolation. Furthermore, we estimated that Colombia, Brazil, the United States, and Peru are the world frontrunners in mpox duplication time (estimated between 6.4 and 8.8) and effective reproductive number (estimated between 2.7 and 3.8). In addition, Brazil reported its first case of inverse zoonosis in a dog and Peru its first autochthonous MPXV lineage, B.1.6. LAC has become the epicenter of the 2022 mpox epidemic, with Brazil and Peru emerging as the new mpox hot zones. Therefore, LAC countries must join efforts to control this epidemic and overcome the challenges of vaccine inequity and stigmatization.