Estuaries are among the most valuable aquatic systems by their services to human welfare. However, increasing human activities at the watershed along with the pressure of climate change are fostering the co-occurrence of multiple environmental drivers, and warn of potential negative impacts on estuaries resources. At present, no clear understanding of how coastal ecosystems will respond to the non-stationary effect of multiple drivers. Here we analysed the temporal interaction among multiple environmental drivers and their changing priority on shaping phytoplankton response in the Bahía Blanca Estuary, SW Atlantic Ocean. The interaction among environmental drivers and the number of significant direct and indirect effects on chlorophyll concentration increased over time in concurrence with enhanced anthropogenic stress, changing winter climate and wind patterns. Over the period 1978-1993, proximal variables such as nutrients, water temperature and salinity, showed a dominant effect on chlorophyll, whereas in more recent years (1993-2009) climate signals (SAM and ENSO) boosted indirect effects through its influence on precipitation, wind, water temperature and turbidity. Turbidity emerged as the dominant driver of chlorophyll while in recent years acted synergistically with the concentration of dissolved nitrogen. As a result, chlorophyll concentration showed a significant negative trend and a loss of seasonal peaks reflecting a pronounced reorganisation of the phytoplankton community. We stress the need to account for the changing priority of drivers to understand, and eventually forecast, biological responses under projected scenarios of global anthropogenic change.