Based on multidisciplinary data, including seismological and geodetic observations, as well as seismic reflection profiles and gravity maps, we analysed the pattern of crustal deformation and active tectonics in the Sicily Channel, a key observation point to unravel the complex interaction between two major plates, Nubia and Eurasia, in the Mediterranean Sea. Our data highlight the presence of an active ~ 220-km-long complex lithospheric fault system (here named the Lampedusa-Sciacca Shear Zone), approximately oriented N-S, crossing the study area with left-lateral strike-slip deformations, active volcanism and high heat flow. We suggest that this shear zone represents the most active tectonic domain in the area, while the NW-SE elongated rifting pattern, considered the first order tectonic feature, appears currently inactive and sealed by undeformed recent (Lower Pleistocene?) deposits. Estimates of seismological and geodetic moment-rates, 6.58 × 1015 Nm/year and 7.24 × 1017 Nm/year, respectively, suggests that seismicity accounts only for ~ 0.9% of crustal deformation, while the anomalous thermal state and the low thickness of the crust would significantly inhibit frictional sliding in favour of creeping and aseismic deformation. We therefore conclude that a significant amount of the estimated crustal deformation-rate occurs aseismically, opening new scenarios for seismic risk assessments in the region.