European estuaries are subjected to a large spectrum of anthropogenic pressures, which are known to have additive, antagonistic, synergistic and multiplicative impacts on the functioning of ecological systems. Understanding the pressure-impact relationships and the interactions effects among pressures are essential requirements to develop accurate strategy of restoration. In this context, a key component is to identify priority actions and sort them to maximize the expected ecological improvement at each step of restoration. This study investigated the impact of multiple pressures in fish communities for 91 European transitional waters, with the aim of assisting managers to develop efficient strategies of restoration. Twenty environmental indicators were selected to assess the intensity of 10 major pressures affecting estuaries. Random Forest regression method was used to predict the fish ecological status of systems, assessed by the Ecological Quality Ratio (EQR), according to the combined effects of indicators. The relative importance of indicators and their effects on the partial ecological response was evaluated, highlighting gradual nonlinear relationships and thresholds shifts. The expected improvements of EQR were investigated for both individual and combined measures of restoration using the predictive performances of the random forest. The effects of pairwise restoration events, i.e. additive or interactive, were defined by comparing the EQR improvement for separated (i.e. sum of individual predictions) and combined events of pressure restoration. Strict additive effects were highlighted for only 7 pairs of pressures, whereas the 38 other pairs showed significant interactions suggesting antagonistic and synergistic effects. Our results showed that the fish ecological status of estuaries cannot be summarized by the sum of the individual responses for each pressure. This observation should be considered to define the priority order of pressures in management restoration strategies.