Macrosystems are integrated human–natural systems, in recognition of the fact that virtually every natural system on Earth influences and is influenced by human activities, even over long distances. It is therefore crucial to incorporate inherent properties of broad‐scale systems, such as human–nature connectivity and feedbacks at multi‐scales, into macrosystems biology studies. Here, we propose the “metacoupling” framework as a macrosystems biology approach. This framework incorporates the study of ecological and socioeconomic dimensions and their interactions within, between, and among adjacent and distant locations. We present examples highlighting that (1) human activities are increasing multi‐scale interactions; (2) the increase in frequency and intensity of distant interactions reduces the importance of proximity as a dominant factor connecting systems; and (3) metacoupling generates both ecological and socioeconomic feedbacks, with profound impacts. The metacoupling framework discussed here can advance macrosystems biology, create opportunities for innovative scientific discoveries, and address global challenges.