We propose a long-term view of the evolution of human-environment interactions within Mediterranean wetlands, from prehistory to the present day, based on available published works. Our aim is to consider the sustainable use of these landscapes, past, present, and future, integrating perspectives from archaeology, ecology, and sustainable development. After briefly introducing the physiographic and ecological processes that characterize Mediterranean wetlands and the ecosystem services they provide to human populations, we consider their significance for three major questions in European archaeology: the Neanderthal extinction and the spread of modern humans, the introduction and spread of agriculture, human environmental impact since the Bronze and Iron ages. We then proceed with historical evidence of intentional transformation of Mediterranean wetlands by means of land reclamation, from the Classical to Medieval periods and into Modern times, before considering the current state of Mediterranean wetlands and the challenges they are facing in the present day. The preservation of wetlands has now become a priority issue at European level and generates concern for local communities and governing bodies, concerning biodiversity, maintenance of key services and cultural preservation. Based on the review of key events in the dynamic relationship between human populations and Mediterranean wetlands, we end by exploring available initiatives, tools and strategies to assess and support their conservation, governance and sustainable development, present and future.