A systematic review of animal leptospirosis, a global emerging bacterial zoonotic disease, was performed to advance the understanding of the pathogen’s presence, dynamics, and potential risks to human health in the southern United States. Seroprevalence and bacterial isolation data were identified in studies that span >100 years, and findings suggest that the pathogen is widely distributed across the southern United States and across animal species. The analysis found that disease frequency is affected by habitat, animal interactions, and changes in environmental conditions. Collaboration across public and animal health fields can inform surveillance, reduce transmission between animals and humans, and enhance prevention efforts. Abstract Leptospirosis is a zoonotic disease with symptoms in humans and animals, ranging from subclinical to serious and fatal. The disease occurs worldwide, but there is limited recognition of the public and animal health risks it poses in the southern United States. A systematic review of the frequency of animal leptospirosis in 17 states and jurisdictions covering the southern continental United States was performed to advance our understanding of the pathogen’s distribution and identify transmission patterns that could be targeted for prevention efforts. Fifty-two articles, spanning >100 years, met the analysis criteria. A wide range of techniques were used to measure seroprevalence and isolate the bacteria. The assessment identified exposure to Leptospira spp and Leptospira spp infection among a diverse range of species, spanning 22 animal families within 14 states, suggesting that the pathogen is distributed throughout the southern region. Disease frequency trends were assessed among animals in various habitats (all habitats, nonwild habitats, and wild habitats). The frequency of Leptospira spp detection in animals in wild habitats increased slightly over time (<0.2%/year). We identified reports of 11 human leptospirosis illness clusters and outbreaks in the southern United States. Exposure to potentially contaminated surface waters were documented for at least seven of the events, and interactions with infected or likely infected animals were documented for at least six of the events. This analysis highlights the need for stronger partnerships across the public and animal health fields to enhance diagnostics, surveillance, and reporting. The early identification of leptospirosis in animals may serve as an indicator of environmental contamination and trigger prevention measures, such as vaccinating companion animals and livestock, use of potable water, and the wearing of waterproof protective clothing near water that may be contaminated.