Conserving wildlife while simultaneously meeting the resource needs of a growing human population is a major sustainability challenge. As such, using combined social and environmental perspectives to understand how people and wildlife are interlinked, together with the mechanisms that may weaken or strengthen those linkages, is of utmost importance. However, such integrated information is lacking. To help fill this information gap, we describe an integrated coupled human and natural systems (CHANS) approach for analyzing the patterns, causes, and consequences of changes in wildlife population and habitat, human population and land use, and their interactions. Using this approach, we synthesize research in two sites, Wolong Nature Reserve in China and Chitwan National Park in Nepal, to explicate key relationships between people and two globally endangered wildlife conservation icons, the giant panda and the Bengal tiger. This synthesis reveals that local resident characteristics such as household socioeconomics and demography, as well as community-level attributes such as resource management organizations, affect wildlife and their habitats in complex and even countervailing ways. Human impacts on wildlife and their habitats are in turn modifying the suite of ecosystem services that they provide to local residents in both sites, including access to forest products and cultural values. These interactions are further complicated by human and natural disturbance (e.g., civil wars, earthquakes), feedbacks (including policies), and telecouplings (socioeconomic and environmental interactions over distances) that increasingly link the focal systems with other distant systems. We highlight several important implications of using a CHANS approach for wildlife research and conservation that is useful not only in China and Nepal but in many other places around the world facing similar challenges.