Tuberculosis (TB) in humans is a global public health concern and zoonotic TB is also receiving more attention as a potential human threat. However, discovery of animal cases of Mycobacterium tuberculosis (M. tb), especially in multi-host settings, could also have significant implications for public health, veterinary disease control activities, and conservation. This paper describes a fatal case of M. tb infection in a free-ranging African elephant in a high human TB burden region discusses diagnostic techniques, and reviews current knowledge on elephant TB. Necropsy revealed extensive granulomatous pneumonia, from which M. tb was isolated and identified as a member of LAM3/F11 lineage, found in human patients in South Africa. These findings are contextualized within a framework of emerging human TB disease in wildlife globally and highlight the potential consequences of ignoring principles of One Health in addressing the reverse zoonoses that can lead to introduction of human pathogens into wildlife.