The Vaccarès Lagoon System, located in the central part of the Rhône Delta (France), is a complex shallow coastal lagoon, exposed to a typical Mediterranean climate and a specific hydrological regime affected by man-controlled exchanges with the sea and agricultural drainage channels. In this article, we report the results obtained by a series of monitoring programs, with different spatial and temporal resolutions. Long-term datasets from 1999 to 2019 with data collected on a monthly basis and a high spatial resolution highlighted the significant spatial heterogeneity in salinity regimes, and helped to determine the long-term evolution of the total mass of dissolved salt. High-frequency surveys allowed to characterize the water levels and salinity dynamics seasonal response to (i) the exchanges with the Mediterranean Sea, (ii) the exchanges with agricultural drainage channels, and (iii) the rain and evaporation. In addition, wind effects on salinity variations are also explored. This work shows how different spatial and temporal monitoring strategies provide complementary information on the dynamic of such a complex system. Results will be useful and provide insight for the management of similar lagoon systems, accommodating for both human activities and ecological stakes in the context of global change.