We present a palaeoenvironmental study of the Castelló lagoon (NE Spain), an important archive for understanding long-term interactions between dynamic littoral ecosystems and human management. Combining geochemistry, mineralogy, ostracods, diatoms, pollen, non-pollen palynomorphs, charcoal and archaeo-historical datasets we reconstruct: 1) the transition of the lagoon from a marine to a marginal environment between ~3150 cal BC to the 17th century AD; 2) fluctuations in salinity; and 3) natural and anthropogenic forces contributing to these changes. From the Late Neolithic to the Medieval period the lagoon ecosystem was driven by changing marine influence and the land was mainly exploited for grazing, with little evidence for impact on the natural woodland. Land-use exploitation adapted to natural coastal dynamics, with maximum marine flooding hampering agropastoral activities between ~1550 and ~150 cal BC. In contrast, societies actively controlled the lagoon dynamics and become a major agent of landscape transformation after the Medieval period. The removal of littoral woodlands after the 8th century was followed by the expansion of agrarian and industrial activities. Regional mining and smelting activities polluted the lagoon with heavy metals from the ~11th century onwards. The expansion of the milling industry and of agricultural lands led to the channelization of the river Muga into the lagoon after ~1250 cal AD. This caused its transformation into a freshwater lake, increased nutrient load, and the infilling and drainage of a great part of the lagoon. By tracking the shift towards an anthropogenically-controlled system around ~750 yr ago, this study points out Mediterranean lagoons as ancient and heavily-modified systems, with anthropogenic impacts and controls covering multi-centennial and even millennial timescales. Finally, we contributed to the future construction of reliable seashell-based chronologies in NE Spain by calibrating the Banyuls-sur-Mer ΔR offset with ceramic imports from the Emporiae archaeological site.