Benthic-pelagic coupling plays a pivotal role in aquatic ecosystems but the effects of fishery driven interactions on its functioning has been largely overlooked. Disentangling the benthic-pelagic links including effects of mixed fisheries, however, needs sketching a whole description of ecosystem interactions using quantitative tools. A holistic food web model has been here developed in order to understand the interplay between the benthic-pelagic coupling and mixed fisheries in a Mediterranean system such as the Strait of Sicily. The reconstruction of the food web required review and integration of a vast set of local and regional biological information from bacteria to large pelagic species that were aggregated into 72 functional groups. Fisheries were described by 18 fleet segments resulting from combination of fishing gears and fishing vessel size. The input-output analysis on the food web of energy pathways allowed identifying effects of biological and fishery components. Results showed that the structure of the Strait of Sicily food web is complex. Similarly to other Mediterranean areas, the food web of the Strait of Sicily encompasses 4.5 trophic levels (TLs) with the highest TLs reached by bluefin tuna, swordfish and large hake and largely impacted by bottom trawling and large longline. Importantly, benthic-pelagic coupling is affected by direct and indirect impacts among groups of species, fleets and fleets-species through the whole trophic spectrum of the food web. Moreover, functional groups able to move on large spatial scales or life history of which is spent between shelf and slope domains play a key role in linking subsystems together and mediate interactions in the Mediterranean mixed fisheries.