Purpose of Review: Leprosy is one of the first pathologies described in the history of mankind. However, the ecology, transmission, and pathogenicity of the incriminated bacilli remain poorly understood. Despite effective treatment freely distributed worldwide since 1995, around 200,000 new cases continue to be detected yearly, mostly in the tropics. This review aims to discuss the unique characteristics of leprosy in Amazonian countries, which exhibit a very heterogeneous prevalence among human and animal reservoirs. Recent Findings: Groundbreaking discoveries made in the last 15 years have challenged the dogmas about leprosy reservoirs, transmission, and treatment. The discovery of a new leprosy causative agent in 2008 and the scientific proof of zoonosis transmission of leprosy by nine-banded armadillos in the southern USA in 2011 challenged the prospects of leprosy eradication. In the Amazonian biome, nine-banded and other armadillo species are present but the lack of large-scale studies does not yet allow accurate assessment of the zoonotic risk. Brazil is the second country in the world reporting the highest number of new leprosy cases annually. The disease is also present, albeit with different rates, in all neighboring countries. Throughout the Amazonian biome, leprosy is mainly found in hyperendemic foci, conducive to the emergence and transmission of drug-resistant strains. Summary: The deepening of current knowledge on leprosy reservoirs, transmission, and therapeutic issues, with the One Health approach and the help of molecular biology, will allow a better understanding and management of the public health issues and challenges related to leprosy in Amazonia.