The Pantanal is the world’s largest freshwater wetland, located in the geographical centre of South America. It is relatively well conserved, and features unique landscapes, ecosystems, and traditional cultural practices, shaped by the dynamic interaction of climatological, hydrological, geological, ecological, and anthropogenic factors. Its ecological integrity is increasingly threatened by human activities, particularly, in the wider catchment area, for example, deforestation, agricultural intensification, and construction of hydropower plants, with implications for local people’s livelihoods. We present a synthesis of current literature on physical, ecological, and human dimensions of environmental change in the wetland, outline key research gaps, and discuss environmental management implications. The literature review suggests that better integration of insights from multiple disciplines is needed and that environmental management could be improved through a better grounding in traditional practices and local perspectives. We conclude with four recommendations: First, future environmental change research should build more strongly on the positive example of a small number of case studies where traditional and local knowledge of the environment was put into a dialogue with scientific knowledge and techniques. Second, we recommend a more explicit consideration of longer temporal scales (>10 years) in environmental change research, making use of oral and written histories, as well as palaeoecological techniques, to understand system responses to different magnitudes of human and climatic pressures, and ultimately, to inform future adaptation activities. Third, we suggest that enhanced stakeholder participation in conceiving and implementing research projects in the Pantanal would strengthen the practical relevance of research in addressing environmental management challenges, livelihood needs, and advocacy processes. Fourth, we call for a more systemic and integrative perspective on environmental education, which encompasses engagement activities between researchers, policy-makers, and citizens, to foster environmental awareness, scientific literacy, and public participation.