The emergence of antimicrobial resistance is arguably the most important threat to human and animal health. The impacts of antimicrobial use can reach far from the site of prescription and wildlife may serve as a conduit for the movement of resistance across landscapes, contributing to the spread of antimicrobial resistance within and between different reservoirs. We compared antimicrobial resistance and life history among wild and domestic species in Chobe, Botswana to explore key attributes and behaviors that may increase exposure and allow resistance to move between humans, animals, and ecosystems. Among 150 fecal samples evaluated from African animals, 41.3% contained Escherichia coli isolates that were resistant to one or two of 10 tested antibiotics, and 13.3% of isolates demonstrated multidrug resistance (three or more antibiotics). Resistance to each of the 10 tested antibiotics was detected among wildlife fecal samples. Resistance was widespread, but not ubiquitous, and isolates from wildlife demonstrated similar patterns of resistance to human E. coli from environmental and clinical sources in the study area. Multidrug resistance was significantly higher in carnivores, water-associated species, and species inhabiting urban areas, suggesting that life history may be key to understanding exposure patterns and transmission dynamics in heterogeneous landscapes.