Environmental mercury (Hg) contamination is an urgent global health threat. The complexity of Hg in the environment can hinder accurate determination of ecological and human health risks, particularly within the context of the rapid global changes that are altering many ecological processes, socioeconomic patterns, and other factors like infectious disease incidence, which can affect Hg exposures and health outcomes. However, the success of global Hg-reduction efforts depends on accurate assessments of their effectiveness in reducing health risks. In this paper, we examine the role that key extrinsic and intrinsic drivers play on several aspects of Hg risk to humans and organisms in the environment. We do so within three key domains of ecological and human health risk. First, we examine how extrinsic global change drivers influence pathways of Hg bioaccumulation and biomagnification through food webs. Next, we describe how extrinsic socioeconomic drivers at a global scale, and intrinsic individual-level drivers, influence human Hg exposure. Finally, we address how the adverse health effects of Hg in humans and wildlife are modulated by a range of extrinsic and intrinsic drivers within the context of rapid global change. Incorporating components of these three domains into research and monitoring will facilitate a more holistic understanding of how ecological and societal drivers interact to influence Hg health risks.