The climate crisis has accelerated the frequency and intensity of droughts in the Mediterranean areas, impacting the hydrology and the ecology of their basins. Maule River is the largest watershed in the Chilean Mediterranean Zone. The growing anthropic and environmental pressure has led to changes in the structure and function of its terrestrial ecosystem. However, little is known about its influence on aquatic ecosystems. The effect of the recent extreme drought on the streamflow and its influence on water quality and the benthic macroinvertebrate community structure were evaluated in the Maule River’s lower section. Beyond temporal and spatial fluctuations, healthy and permanently well-oxygenated waters prevailed in the study area. However, during the megadrought period, evidenced by a significant decrease in both precipitation and river streamflow, a greater salt wedge influence was observed, at least, in the last 7 km of the river. Although with certain asynchrony, a change in the structure of the benthic macroinvertebrate community was observed in the upstream stations. This marinization reveals an increase in the domain of marine taxa associated with the Polychaeta group and a clear decrease in typical freshwater Oligochaeta individuals. This modification in the structure of the benthic community is expected to affect the function of this estuarine system. The results presented here highlight the importance of considering the variability associated with biological components for the management of water resources and related ecosystem services, considering that one of the main problems associated with changes in land use and the pressures caused by the climate crisis is the decrease in the quality and availability of water in this and other Mediterranean basins globally.