The Sea of Marmara is a tectonically active basin that straddles the North Anatolian Fault Zone (NAFZ) that separates the Eurasian and Anatolian tectonic plates. The Main Marmara Fault (MMF), which is part of the NAFZ, contains an approximately 150 km long seismotectonic segment that has not ruptured since 1766. A key question for seismic hazard and risk assessment is whether or not the next displacement along this segment is likely to produce one major earthquake or a series of smaller earthquakes. Geomechanical characteristics such as along-strike variations in rock strength may provide an important control on seismotectonic segmentation. We find that variations in lithospheric strength throughout the Marmara Region control the mechanical segmentation of the MMF and help explain its long-term characteristics of seismotectonic segmentation. In particular, a strong crust that is mechanically coupled to the upper mantle spatially correlates with aseismic patches where the MMF bends and changes its strike in response to the presence of high-density lower crustal bodies. Between the bends, mechanically weaker crustal domains that are decoupled from the mantle indicate a predominance of creeping. These results are highly relevant for the ongoing debate regarding the characteristics of the Marmara seismic gap, especially in view of the seismic hazard (Mw > 7) in the densely populated Marmara Region.