A number of marine mammal populations is currently threatened by their interactions with fisheries. The present study aimed to provide insights into the severity of potential impacts of operational and biological interactions between top predators and fisheries, in the Bay of Biscay region. Our approach was to modify an Ecopath with Ecosim (EwE) model describing the overall structure and function of the ecosystem by including landings and discards of exploited stocks and estimations of the bycatch of non-target compartments. Second, a set of ecological indices and a trophic level (TL)-based model (EcoTroph, ET) were derived from the EwE model. ET was used to simulate the effects of increasing fishing pressure on the ecosystem and, more particularly, on top predators. The Bay of Biscay was demonstrated to be not far from overexploitation at the current fishing rate, this phenomenon being particularly noticeable for the highest TLs. Within the toothed cetacean community, bottlenose dolphins appeared the most sensitive to resource depletion, whereas common dolphins and harbour porpoises were most impacted by their incidental captures in fishing gears. This study provides a methodological framework to assess the impacts of fisheries on ecosystems for which EwE, or other ecosystem models, already exist.