The Amik Basin in the Eastern Mediterranean region occupied since 6000-7000 BC has sustained a highly variable anthropic pressure culminating during the late Roman Period when the Antioch city reached its golden age. The present 6-m-long sedimentary record of the Amik Lake occupying the central part of the Basin constrains major paleoenvironmental changes over the past 4000 years using multi-proxy analyses (grain size, magnetic susceptibility, and x-ray fluorescence (XRF) geochemistry). An age model is provided by combining short-lived radionuclides with radiocarbon dating. A lake/marsh prevailed during the last 4 kyr with a level increase at the beginning of the Roman Period possibly related to optimum climatic condition and water channeling. The Bronze/Iron Ages are characterized by a strong terrigenous input linked to deforestation, exploitation of mineral resources, and the beginning of upland cultivation. The Bronze/Iron Age transition marked by the collapse of the Hittite Empire is clearly documented. Erosion continued during the Roman Period and nearly stopped during the early Islamic Period in conjunction with a decreasing population and soil depletion on the calcareous highland. The soil-stripped limestone outcrops triggered an increase in CaO in the lake water and a general decrease in ZrO2 released in the landscape that lasts until the present day. During the Islamic Period, pastoralism on the highland sustained continued soil erosion of the ophiolitic Amanus Mountains. The Modern Period is characterized by a higher pressure particularly on the Amanus Mountains linked to deforestation, road construction, ore exploitation, and drying of the lake for agriculture practices.