Tuberculosis continues to represent a severe public health problem in the Region of the Americas, even more so in the case of indigenous peoples, whose TB incidence is much higher than that of the general population. To achieve tuberculosis control in these communities, it is necessary to respond to communities’ diverse needs from an intercultural perspective that allows the application of a holistic approach—from a standpoint of equality and mutual respect—and considers the value of their cultural practices. In the Region of the Americas, although there has been progress toward recognizing the need for an intercultural approach to health services, obstacles rooted in discrimination, racism, and the exclusion of indigenous peoples and other ethnic groups persist. To respond to this situation, the Pan American Health Organization (PAHO) prepared this guidance which––based on an intercultural approach in accordance with the priority lines of the current PAHO Policy on Ethnicity and Health and its practical development in the Region’s indigenous populations––represent a support tool for implementing the End TB Strategy. This publication integrates PAHO’s accumulated experience and best practices developed by its Member States in recent years, including discussions and experiences shared in regional meetings on the issue, and emphasizes innovation and social inclusion. This requires an urgent shift away from traditional paradigms, taking specific actions that gradually reduce TB incidence and moving toward effective multisectoral actions that have proven effective in quickly containing the epidemic. This publication integrates PAHO’s accumulated experience and best practices developed by its Member States in recent years, including discussions and experiences shared in regional meetings on the issue, and emphasizes innovation and social inclusion. This requires an urgent shift away from traditional paradigms, taking specific actions that gradually reduce TB incidence and moving toward effective multisectoral actions that have proven effective in quickly containing the epidemic.