The Calabrian Arc subduction-rollback system along the convergent Africa/Eurasia plate boundary is among the most active geological structures in the Mediterranean Sea. However, its seismogenic behaviour is largely unknown, mostly due to the lack of seismological observations. We studied low-to-moderate magnitude earthquakes recorded by the seismic network onshore, integrated by data from a seafloor observatory (NEMO-SN1), to compute a lithospheric velocity model for the western Ionian Sea, and relocate seismic events along major tectonic structures. Spatial changes in the depth distribution of earthquakes highlight a major lithospheric boundary constituted by the Ionian Fault, which separates two sectors where thickness of the seismogenic layer varies over 40 km. This regional tectonic boundary represents the eastern limit of a domain characterized by thinner lithosphere, arc-orthogonal extension, and transtensional tectonic deformation. Occurrence of a few thrust-type earthquakes in the accretionary wedge may suggest a locked subduction interface in a complex tectonic setting, which involves the interplay between arc-orthogonal extension and plate convergence. We finally note that distribution of earthquakes and associated extensional deformation in the Messina Straits region could be explained by right-lateral displacement along the Ionian Fault. This observation could shed new light on proposed mechanisms for the 1908 Messina earthquake.