The dynamics of the Sicily Channel and the southern Tyrrhenian Sea are highly influenced by the seasonal variability of the Mediterranean basin-wide circulation, by the interannual variability of the numerous mesoscale structures present in the Channel, and by the decadal variability of the adjacent Ionian Sea. In the present study, all these aspects are investigated using in-situ (Lagrangian drifter trajectories and Argo float profiles) and satellite data (Absolute Dynamic Topography, Sea Level Anomaly, Sea Surface Temperature, wind products) over the period from 1993 to 2018. The availability of long time series of data and high-resolution multi-sensor surface currents allow us to add new details on the circulation features and on their driving mechanisms and to detect new permanent eddies not yet described in literature. The structures prevailing in winter are mainly driven by wind, whereas those prevailing in summer are regulated by topographical forcing on surface currents. The strength of the surface structures located at the western entrance of the Ionian Sea and of the mesoscale activity along the northern Sicily coast is modulated by the large-scale internal variability. The vertical hydrological characteristics of these mesoscale eddies are delineated using the Argo float profiles inside these structures.